PARP inhibitors (PARPi) are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients with germline mutations in *BRCA1* or *BRCA2* are sensitive to PARPi due to their specific DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, resistance to PARPi arises in advanced disease, and determining the optimal use of PARPi within drug combination approaches has been challenging. The preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. This article discusses current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.PARP inhibitors (PARPi) are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients with germline mutations in *BRCA1* or *BRCA2* are sensitive to PARPi due to their specific DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, resistance to PARPi arises in advanced disease, and determining the optimal use of PARPi within drug combination approaches has been challenging. The preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. This article discusses current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.