Type 2 diabetes mellitus (DM) is a major cardiovascular (CV) risk factor and, as such, is considered a coronary artery disease risk equivalent. Although glycemic control is associated with decreased CV events epidemiologically, many prospective clinical trials have failed to conclusively demonstrate that aggressive glycemic control improves the CV prognosis of patients with type 2 DM, especially those with long-standing DM. Many therapies for type 2 DM with widely divergent mechanisms of action are available. Some of these drugs, in addition to their glucose-lowering actions, have properties that may reduce or increase CV events. Agents that lower both insulin resistance and postprandial hyperglycemia while at the same time avoiding hypoglycemia may be beneficial for CV health. This article reviews the evidence regarding the use of these agents and appropriate glycemic control targets for improving the adverse CV prognosis associated with type 2 DM. We conducted a systematic review of English articles using MEDLINE and the Cochrane Controlled Trials Register (1970-2010) using the following search terms: cardiovascular disease, randomized trials, hypoglycemia, and insulin resistance.