Given the array of adverse health consequences of obesity, including increased risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), the Look AHEAD trial (N = 5145) was conducted to test the hypothesis that an intensive lifestyle intervention (ILI) for weight loss would achieve significantly greater reductions in CVD morbidity and mortality than a control condition of diabetes support and education (DSE) among participants with T2DM. A number of significant and long-term improvements were observed for ILI, including body weight, physical fitness and physical function, glucose control, quality-of-life (QoL), and healthcare costs. However, ILI did not significantly reduce CVD-related morbidity/mortality (i.e., CVD death, non-fatal MI, non-fatal stroke, hospitalized angina) after nearly 10 years of follow-up. There was a suggestion of heterogeneity of response based on the history of prior CVD at baseline (p = 0.06). Despite the overall lack of CVD risk reduction, ILI remains important for care of patients with T2DM, particularly when accompanied by medication management. In particular, ILI may be an appealing option for patients wanting to minimize medication intensification. Also, ILI carries with it other potential benefits important to patients (e.g., improvements in physical functioning and QoL). Based on data from other trials, intensive medication management, such as tight glycemic control, is not without potential risks, which should be weighed in making treatment decisions. Future research is needed to determine if results observed in this trial would be replicated among younger patients, those without established T2DM, and/or those with no pre-existing CVD.