Abstract As the search for suitable cancer drug targets becomes ever more difficult, the need for novel approaches to this problem is becoming more apparent. Although first proposed in the 1940s, it is only recently that the concept of using synthetic lethality (SL) to design new therapeutic approaches is being tested both in the laboratory and in the clinic. Two genes or proteins are synthetic lethal when deficiency in either is compatible with cellular viability but loss of both is not. Where one partner of a synthetic lethal relationship is a tumor suppressor gene that is lost in tumors, the other synthetic lethal partner, once identified, becomes a candidate drug target. Using this approach, we have identified PARP inhibition as being SL with loss of either the BRCA1 or BRCA2 tumor suppressor genes and clinical trials testing this approach are now showing considerable promise. Using this and other examples, I will illustrate how the SL approach can be exploited, how novel targets can be identified and how tumor types as diverse as colorectal, breast, prostate, and endometrial cancer could be treated using a SL approach. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr IA22.