Impaired genomic stability is a hallmark of many cancers, with the DNA damage response (DDR) mechanisms serving as critical safeguards for maintaining genomic integrity. These intricate DDR networks, encompassing various DNA repair and damage checkpoint pathways, are essential for regulating the cell cycle, immune responses, and apoptosis. Notably, defects in DDR pathways, particularly those involving BRCA1/2 mutations, present exploitable vulnerabilities for targeted therapies such as PARP inhibitors (PARPi). This review explores the mechanisms by which PARPi function as cancer therapies, focusing on their ability to inhibit DNA repair processes and induce tumor cell death. It also examines the current landscape of PARPi clinical trials and their application across various cancer types. In addition, we discuss emerging DDR inhibitors, including CHK1/2, ATR, ATM, RAD51, APE1, and WEE1, many of which act by inhibiting DNA repair and damage checkpoints. These inhibitors selectively target malignant cells that are deficient in checkpoint function, thereby inducing replication stress and mitotic catastrophe. While DDR inhibitors hold great potential as standalone therapies or in combination with chemotherapy, immunotherapy, and radiation, challenges persist, including overlapping toxicities and damage to healthy tissues. This review aims to illuminate the rapidly advancing field of DDR-based targeted cancer therapies, emphasizing their potential to revolutionize treatment approaches and improve patient outcomes.