Central nervous system (CNS) infections are caused by diverse microorganisms, including viruses, bacteria, fungi, and parasites. Viruses are the main cause of encephalitis, with an estimation of ∼1.4 million cases and ∼90 000 deaths globally in 2019 [1]. Bacterial meningitis causes ≥ 1.2 million cases per year worldwide, and without adequate treatment, the fatality rates can reach up to 70% [2]. Fungal infections of the central nervous system (FI-CNS) affect ∼1.9 million people globally, resulting in ∼1.6 million deaths annually [3]. They are severe, difficult to treat, and usually life-threatening conditions that require rapid and aggressive medical treatment. FI-CNS involve different clinical manifestations, including meningitis, encephalitis, hydrocephalus, cerebral abscesses, and stroke. The frequency of FI-CNS is rising due to an increase in individuals with immunosuppression, including HIV/AIDS, cancer, and organ transplantation 4, 5, among others. Cryptococcus neoformans is the most common etiological agent of fungal meningitis (70.1%) in the United States (U.S.), followed by Coccidioides species (16.4%), Histoplasma capsulatum (6.0%), and Candida species (7.6%) [6]. Coccidioides and H. capsulatum cause meningitis in endemic areas, while Candida species mostly affect premature babies and individuals with CNS prosthetic devices (e.g. shunts or drains). Molds, mainly Aspergillus and Mucorales (e.g. Rhizopus, Mucor, etc.) species, can cause CNS infections that are characterized by localized mass lesions in brain tissue. Less common and under special circumstances, species of Fusarium, Scedosporium, or dematiaceous (pigmented) molds cause CNS infections. For example, the black-pigmented mold Exserohilum rostratum caused the largest-ever U.S. healthcare-associated outbreak when 753 cases of meningitis were reported in patients who received epidural injections of methylprednisolone, which was contaminated during the manufacturing process in a compounding pharmacy, resulting in 64 deaths [7]. Despite the great number of different FI-CNS agents, only some possess well-defined treatment standards (e.g. cryptococcal meningitis and CNS aspergillosis). Hence, a prompt diagnosis of fungal infection together with correct identification of the causative agent is needed to allow the administration of effective therapy in patients with FI-CNS to reduce the associated high mortality [8]. In this review, we discuss the (1) challenges faced by current antifungal drugs, (2) status of the recommended standard of care for treatment of cryptococcal meningitis, (3) potential antifungal therapeutic candidates, and (4) novel molecular targets to prevent FI-CNS.