The recognition that insulin resistance has a pivotal role in the pathogenesis of polycystic ovary syndrome (PCOS) revolutionized our understanding of this complex disorder. PCOS causes major metabolic and reproductive morbidities, including substantially increased risk for type 2 diabetes mellitus and the metabolic syndrome. Insulin-sensitizing drugs (ISDs) ameliorate reproductive abnormalities, restore ovulation and regular menses, increase pregnancy rates and reduce androgenic symptoms in affected women with PCOS. Accordingly, ISDs, specifically metformin, have been widely adopted as therapy for this condition. A recent, large, randomized, multicenter, clinical trial that assessed live-birth rates rather than surrogate end points suggested that metformin alone is inferior to clomiphene citrate in treating infertility associated with PCOS. There is, furthermore, no evidence to support the use of metformin during pregnancy to prevent spontaneous abortions or gestational diabetes mellitus in women with PCOS. Renewed safety concerns about thiazolidinediones followed recent studies that reported increased cardiovascular morbidity with these agents. These concerns might preclude thiazolidinedione use in otherwise healthy women with PCOS. Finally, although ISDs improve insulin action and cardiovascular disease risk, there is no evidence that they provide long-term health benefits in PCOS. This article discusses the role of ISDs in PCOS in light of these new data.