The exploitation of synthetic lethality in BRCA-deficient tumor carriers using potent inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP)-1 has led to an enthusiastic response among basic scientists, oncologists and pharmaceutical companies. However, accumulating evidence demonstrates that resistance to these drugs develops in tumors in both preclinical and clinical settings. Here, I focus on literature dealing with resistance to these drugs and discuss the molecular mechanisms involved, such as restoration of BRCA function, upregulation of nonhomologous end-joining-dependent DNA repair, induction of P-glycoprotein expression and epigenetic deregulation. Clinical implications of resistance to PARP1 inhibitors are also discussed.