Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities. Homologous recombination (HR)-deficient tumors are hypersensitive to poly-(ADP)-ribose polymerase inhibitors (PARPi)-induced DNA damage. Therefore, PARPi have shown great promise in the clinic, but rates of pre-existing and acquired resistance are high.Four main mechanisms of PARPi resistance have been characterized, representing those that impact on (i) cellular availability of the inhibitor, (ii) the activity and abundance of PAR chains, (iii) reactivation of HR, and (iv) replication fork protection.Loss of the 53BP1–RIF1–REV7–Shieldin axis, that is involved in non-homologous end-joining repair of DNA double-strand breaks, reactivates resection and HR in BRCA1-deficient cells, leading to PARPi resistance. Shieldin seems to shield broken ends by blocking access to nucleases. The exact mechanism by which Shieldin controls resection needs to be resolved.Studies in large patient cohorts will need to clarify the clinical relevance of the different PARPi resistance mechanisms. Furthermore, research on resistance mechanisms will drive future genetic screening of resistance factors to guide therapy decisions.