Despite improvement of microvascular outcomes as a consequence of optimal glucose control in patients with type 2 diabetes, prevention of macrovascular complications is still a major challenge. Of interest, large-scale intervention studies (Action to Control Cardiovascular Risk in Diabetes, Action in Diabetes and Vascular Disease-Preterax and Diamicron Modified Release Controlled Evaluation and Veterans Affairs Diabetes Trial) comparing standard therapy versus more intensive glucose-lowering therapy failed to report beneficial impacts on macrovascular outcomes. Consequently, it is currently under debate whether the high doses of exogenous insulin that were administered in these trials to achieve strict target glucose levels could be responsible for these unexpected outcomes. Additionally, a potential role for plasma insulin levels in predicting macrovascular outcomes has emerged in patients with or without type 2 diabetes. These observations, combined with evidence from in vitro and animal experiments, suggest that insulin might have intrinsic atherogenic effects. In this review, we summarize clinical trials, population-based studies as well as data emerging from basic science experiments that point towards the hypothesis that the administration of high insulin doses might not be beneficial in patients with type 2 diabetes and established macrovascular disease.