Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. This would represent one of the first clinically implemented examples of a synthetic lethal approach for cancer treatment. However, there are still unanswered questions surrounding PARP inhibitors, namely the levels of specificity and potency that are required to elicit BRCA selectivity. The recent identification of mechanisms of cellular resistance to PARP inhibitors may provide indications as to how these drugs may be best used in the clinic.