It is well known that improved metabolic control significantly reduces both micro- and macrovascular complications in diabetes. As it relates to specific treatment of type 2 diabetes mellitus, clinicians have traditionally initiated lifestyle intervention and progressed therapy using various drug treatments first as monotherapy and then as combination therapy throughout the course of the disease. This “stepwise” strategy has not always achieved the desired outcome of normal glycemic control; consequently, several clinical problems, such as hypoglycemia, weight gain and postprandial hyperglycemia, persist. However, new therapies that improve glycemic control and have favorable effects to address the unmet clinical problems have recently been developed or are still in development. These therapies include 2 classes of incretin-directed therapy, the dipeptidyl peptidase-4 inhibitors and the glucagon-like peptide-1 agonists, which help restore physiologic levels and activity of the incretin glucagon-like peptide-1. Also in development are additional therapies that have effects on the kidney to promote glucose excretion. These therapies are proposed to treat the key metabolic abnormalities associated with type 2 diabetes mellitus and minimize the side effects noted with conventional therapies.