Background: Several recent meta-analyses of adverse event data from randomized controlled trials with rosiglitazone reveal a possible association between this thiazolidinedione and an increased risk of ischemic myocardial events. This has led to debate on the overall clinical benefit of glitazone therapy for type 2 diabetes. Pioglitazone, on the other hand, has the most extensive cardiovascular outcomes database of all current glucose-lowering therapies, including a large prospective randomized controlled trial designed specifically to assess cardiovascular outcomes (PROactive). The available data suggest that pioglitazone is associated with a reduction in macrovascular risk. Aims: In this review, we highlight some of the key factors that need to be considered when assessing the net clinical benefit of thiazolidinediones, focussing on both class effects and those specific to either rosiglitazone or pioglitazone. Results: For pioglitazone there appears to be no increase in the risk of overall macrovascular events and no adverse clinical consequences of developing signs of heart failure. Furthermore, there is good evidence of significant benefit regarding the composite of death, MI or stroke. Conclusion: The benefits seen with pioglitazone appear to outweigh the risks.