Significant advances in the treatment of type 2 diabetes mellitus (T2DM) include the implementation of prevention efforts aimed at delaying progression of glucose intolerance to overt diabetes mellitus (DM) and the development of new classes of blood glucose-lowering medications to supplement existing therapies. While the current management approach for T2DM continues to encompass traditional drugs that focus on β-cell failure and/or insulin resistance, newer agents that target other defects (eg, incretin deficiency/resistance) are increasingly incorporated. Furthermore, the effect of therapies on associated comorbidities (eg, dyslipidemia, hypertension, obesity, hypercoagulability) has become an additional therapeutic focus. This article provides a discussion of specific pharmacologic agents, based on guidelines from the American Diabetes Association/European Association for the Study of Diabetes and relevant clinical studies. An extensive update on the newest drugs (eg, incretin-based therapies, amylin agonists) and managed care aspects of diabetes care is also included.