Cancer is a lethal and dangerous disease which affects millions of people's lives in the world. Based on the American Cancer Society, 1.9 million new instances of cancer was reported and 60,920 cancer-related deaths was happen in the US by the end of 2023 [1]. Conventional cancer therapies involve radiation therapy, chemotherapy, and surgery. When cancer is detected early, surgery can be quite successful; however, when the cancer is advanced or has spread, surgery is not as beneficial. Radiation therapy has a good therapeutic impact on early-stage cancer and doesn't require surgery, but it comes with hazardous side effects and doesn't eradicate cancer cells outside of the radiation area. Chemotherapy helps patients live longer, but many medications are harmful to healthy cells, which drastically lowers patients' quality of life [2]. Despite the competition of macromolecule drugs such as nucleic acids, polypeptides, mAbs (monoclonal antibodies) and antibody–drug conjugates, the use of small-molecules as anti-cancer which target the new genes or action mechanism, will remain to be the most common cancer treatment due to their unique advantages [3]. TRK kinases are a class of cell surface receptor tyrosine kinases which are expressed by NTRK (neurotrophic factor receptor kinases) genes in the nervous system [4,5]. There are three subtypes in this family: TRKA, TRKB, and TRKC that encoded by the TRK1, TRK2, and TRK3 genes, respectively [6,7]. Each subtype activates the TRK enzymes by binding to a specific cognate ligand (neurotrophin). Therefore, NGF (nerve growth factor) activates TRKA, neurotrophin-4 and BDNF (brain-derived growth factor) activates TRKB, and NT-3 (neurotrophin-3) activates TRKC [8]. Signal transduction pathways, containing RAS-MAPK and PI3K-AKT, are triggered by activated TRK enzymes and control the cell growth, cell cycle, survival, apoptosis, differentiation of nervous system and nerve cells [9]. Furthermore, the appetite, memory and perception of pain in post-embryonic developing infants are related to TRK enzymes in the nervous system [7]. However, NTRK has been identified as a fusion oncogene in cancer. For example, (ETV6-NTRK3 (ETS translocation variant 6-NTRK3) in secreted mesoblastic congenital fibrosarcoma [10,11] and TPM3-NTRK1 (tropomyosin 3-NTRK1) in cancer of colorectal can mediate the same downstream pathway leading to cancer progression [12]. A variety of cancers have displayed TRK overexpression, such as cutaneous (for example, basal cell carcinoma), lung and breast cancers, cylindroma, neuroblastoma and etc. In patients with neuroblastoma, overexpression of TRKA and TRKC enzymes is powerfully predictive of favorable results, while expression of TRKB enzyme is mainly observed in higher-grade tumors which also harbor MYCN amplification [13]. TRK enzymes are attractive “pan-cancer” targets in NTRK fusion-positive adult and pediatric cancers. Since majority of oncogenic NTRK fusions eliminate or alter the extracellular domain, so, traditional mAb therapy is ineffective. Therefore, the main method for targeting of oncogenic NTRK fusions is concentrated on small molecule TRK inhibitors [14]. The increasing of NTRK fusion-positive cancers related to TRK receptor activity, introducing TRK inhibitor agents as appropriate therapeutic agents in cancer therapy [15]. TRK inhibitors can be divided into four different subtypes (A) type I, (B) type II, (C) type III, and (D) type IV according to ligand binding interactions. Type I TRK inhibitor agents bind to the ATP-binding pocket and so are ATP competitive such as most of clinical studies' TRK inhibitors. TRK inhibitors of Type II are ATP noncompetitive and display pseudocompetitive or noncompetitive binding kinetics. Inhibitors of Type II bind to the ATP-binding pocket and moreover to a neighboring allosteric site. TRK inhibitors of Type III bind to outside of the ATP-binding pocket in the kinase domain. Inhibitors of Type III, unlike inhibitors of type II are true inhibitors of allosteric that help reach selectivity between TRK isoforms. TRK inhibitors of Type IV bind to an area other than the kinase domain [16]. TRK inhibitors have displayed notable clinical efficiency and durable responses in patients with cancers harboring NTRK fusions that result in significant clinical benefits, containing prolonged progression-free survival and tumor shrinkage. Therefore, TRK inhibitors are promising options for patients with metastatic or advanced cancers which harbor these specific genetic alterations [17]. Many small molecules as TRK inhibitors have been evaluated that many of them are currently under clinical trials [4,14]. Larotrectinib (LOXO-101, 1) and entrectinib (PXDX-101, 2) as first-generation TRK inhibitors (Fig. 1), were licensed in 2018 and 2019, by the FDA, respectively that have displayed significant clinical benefits to treat of solid tumors that are TRK-fusion positive [18]. But, mutation of TRK kinases led to resistance to both drugs [14]. NTRK fusion-positive tumors have shown off-target and on-target resistance mechanisms against TRK inhibition. Mechanisms of on-target resistance can be attributed to mutations of the NTRK kinase domain, leading to substitutions of amino acid [19]. The mutations recorded involved the xDFG motif mutations for example TRKCG696A and TRKAG667C/S, the SF (solvent-front) mutations for example TRKCG623R and TRKAG595R, and the mutations of gatekeeper (GK) for example TRKAF589L. The residues changed as a result of the mutations which sterically prevented the binding of the TRK inhibitor to the ATP binding pocket [14]. To overcome these resistances, second-generation of TRK inhibitors were developed such as macrocycle-based Loxo-195 (selitrectinib, 3) in phase II clinical trials) and repotrectinib (TPX-0005, 4) in phase III clinical trials) with significant clinical activities against GK and SF mutations mediated resistances but with limited activity against cancers with acquired xDFG mutations [20]. Off-target resistance or bypass resistance mechanisms are known because of the non-TRK oncoproteins activation, for example with activating KRAS or BRAF mutations., In vitro models and preclinical information have displayed which activation of IGF1R can cause TRK inhibitor resistance. Nevertheless, recently, mechanisms of TRK-extrinsic resistance were recognized in patient collected samples after resistance to previous TRK inhibitors [19]. Dual-targeting/Multi-targeting of human oncoproteins through a single drug compound exhibits a logical, efficient and alternative method to drug combinations. Many numbers of published articles about targeting dual/multi proteins in the last years, indicates an increasing interest in this approach. [21]. In the other words, because of the multimodal nature of cancer, simultaneous inhibition of two or more targets by a single compound is an effective and beneficial approach against cancer [22]. Presently, there are two strategies for designing of the multi-targeting therapeutics including combination drug therapy and multiple-targeting drugs. Combination drug therapy is a synergistic or additive effect of multiple drugs via acting on separate targets [23]. Multi-targeting therapy contains discovering a single compound which can simultaneously act on two or more targets [24,25]. A dual-target inhibitor can cause distinct benefits such as more expected pharmacokinetics, decreased the possibility of drug interactions, and better patient compliance in comparison to a traditional single-target inhibitor. Cancer therapy with single-target agents are more susceptible to the development of drug resistance with time, thus cause to diminish the efficacy of anti-tumor drugs. Using of dual-target inhibitor compounds can decrease this issue via targeting of multiple pathways [26]. Many studies have been done on multi-targeting therapy because of their advantages such as overcoming clonal heterogeneity, lesser risk of MDR (multi-drug resistance), reduced drug toxicity, and so lower adverse effects [27]. In this review, structures, synthetic reactions, biological evaluations and in silico studies of dual TRK inhibitors and multi TRK inhibitors were summarized. This review shows that studies on this class of compounds are in the early stages, and in addition to the need for more detailed and extensive studies on each of the targets discussed, there are many other targets that can be studied as co-targets with TRK in the hope of achieving more effective drugs.