Current strategies for the treatment of type 2 diabetes mellitus promote individualized plans to achieve target glucose levels on a patient-by-patient basis while minimizing treatment related risks. Maintaining glycemic control over time is a significant challenge because of the progressive nature of diabetes as a result of declining β-cell function. This article identifies complications of non-insulin treatments for diabetes. The major classes of medications are reviewed with special focus on target population, mechanism of action, effect on weight, cardiovascular outcomes and additional class-specific side effects including effects on bone. Effects on β-cell function are also highlighted.