The year of 2005 was a watershed in the history of poly(ADP-ribose) polymerase (PARP) inhibitors due to the important findings of selective killing in BRCA-deficient cancers by PARP inhibition. The findings made PARP inhibition one of the most promising new therapeutic approaches to cancers, especially to those with specific defects. With AZD2281 and BSI-201 entering phase III clinical trials, the final application of PARP inhibitors in clinic would come true soon. This current paper will review the major advances in targeting PARP for cancer therapy and discuss the existing questions, the answers to which may influence the future of PARP inhibitors as cancer therapeutics.