Several evidences have shown that BRCA mutations increased tumor-cells sensitivity to PARP inhibitors by synthetic lethality leading to an accelerated development of several compounds targeting the PARP enzymes system as anticancer agents for clinical setting. Most of such compounds have been investigated in ovarian and breast cancer, showing promising efficacy in BRCA-mutated patients. Recently clinical studies of PARP-inhibitors have been extended across different tumor types harboring BRCA-mutations, including also “BRCA-like” sporadic tumors with homologous recombination deficiency (HRD). This review summarizes the biological background underlying PARP-inhibition, reporting the results of the most relevant clinical trials carried out in patients treated with PARP inhibitors alone or in combination with chemotherapy. Molecular mechanisms responsible for the occurrence of both primary and acquired resistance have been elucidated, in order to support the development of new treatment strategies.