a, Normal cells have two DDR pathways, A and B. If one pathway (B) is eliminated, genome instability results, which can foster the evolution of a cancer cell. Addition of a inhibitor targeting the second pathway (A) leads to cell death. Normal cells that still retain an active B pathway, however, survive. b, Treatment with a PARP inhibitor selectively kills HR/BRCA-deficient cells. PARP inhibition impairs the repair of SSBs, which are converted to DSBs in S-phase. Such DSBs are effectively repaired by HR in non-cancerous cells but not in BRCA-deficient cells.