Pioglitazone, a thiazolidinedione, improves insulin sensitivity and thus reduces blood glucose. Clinical trials have suggested potential cardiovascular outcome benefits in association with pioglitazone; however, safety concerns are mounting, with recent data suggesting a link between pioglitazone and an increased risk of bladder cancer. There is thus a growing focus on the risk-benefit profile of this agent and hence its potential role in the blood glucose-lowering treatment algorithm for people with type 2 diabetes. There are clear potential outcome benefits associated with pioglitazone. In this review, the authors focus on putting the true risk-benefit profile of pioglitazone into context based on critical appraisal of the currently available evidence.