Insulin resistance, a fundamental pathophysiological abnormality in patients with type 2 diabetes, is associated with increased cardiovascular (CV) disease risk. In diabetes management, the macrovascular impact of antihyperglycemic agents that do not improve insulin sensitivity has generally been disappointing. In contrast, glucose-lowering drugs that work as insulin sensitizing agents have been postulated to reduce CV complications. The data to support this hypothesis have, however, been inconsistent. The impact of thiazolidinediones on macrovascular events is of particular interest. In this review, we discuss the results of trials reporting CV outcomes in patients treated with thiazolidinediones. We focus on the findings of the recent Insulin Resistance Intervention after Stroke trial that demonstrated a beneficial effect of pioglitazone on CV outcomes in stroke patients with insulin resistance. We discuss the Insulin Resistance Intervention after Stroke results and its implications for clinical practice. We discuss the selective use of pioglitazone as secondary prevention to reduce CV risk in insulin resistant patients.