There is interest in the use of DNA repair inhibitors as sensitizers of classic cytotoxic therapy against cancer. However, there is also risk -- theoretical, at least -- that such a strategy may increase the side effects of traditional therapies, including but not limited to treatment-related secondary malignancies. Before being brought to clinical application, therefore, important questions remain to be answered regarding how these therapies will be tailored to achieve benefit without concomitantly increasing harm. A potential solution may involve targeting so-called "synthetic lethalities" in tumor DNA repair pathways; taking advantage of defects acquired in DNA repair pathways during tumorigenesis by targeting alternative repair pathways on which the tumor critically depends. Conceivably, as repair pathways are functional in normal tissue, such targeted therapy should be relatively tumor-specific and non-toxic. We review here the rationale for this strategy, describe examples of its application, and outline potential strengths and weaknesses of this approach. For simplicity, a focus will be placed on the repair of double-strand breaks as a model system, but the conceptual framework is generally applicable to many other pathways of DNA repair.