Poly (ADP-ribose) polymerase inhibitors (PARPi) have transformed the treatment landscape for homologous recombination-deficient (HRD) cancers, particularly those harboring BRCA1/2 mutations, including breast, ovarian, prostate, and pancreatic cancers, by exploiting the synthetic lethality induced by HR deficiency (HRD) and utilizing HRD status as a predictive biomarker. Nevertheless, intrinsic as well as acquired resistance limits their long-term effectiveness. Resistance often develops as a result of several complex mechanisms including the restoration of homologous recombination (HR), stabilization of the replication fork, enhanced drug efflux, loss of PARP1 expression, epigenetic modifications, and changes in the DNA damage response signaling. BRCA1/2-mutant cells, deficient in HR, become reliant on alternative repair pathways like classical non-homologous end joining (c-NHEJ) and microhomology-mediated end joining (MMEJ). Emerging evidence indicates the importance of replication-induced gaps in single-stranded DNA (ssDNA) and alternative pathways of DNA repair in defining PARPi sensitivity and resistance. This review aims to provide a comprehensive analysis of the established and emerging molecular mechanisms of PARPi resistance, and compensatory DNA repair pathways such as MMEJ. In addition to highlighting resistance pathways, the review also discusses strategies focusing on targeting repair mechanisms and replication stress signaling by using novel drugs targeting DNA polymerase theta (POLQ). It subsequently discusses preclinical advancements and ongoing clinical trials. Through linking the molecular determinants of resistance to the translational status and limitations of the latest therapies, this review offers a comparative framework for understanding resistance mechanisms and strategies to restore PARPi sensitivity in cancers with HRD.