Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral glucose utilization are the core defects responsible for the development and progression of type 2 diabetes. However, the pathophysiology of this disease also includes adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity, increased glucagon secretion, enhanced renal glucose reabsorption, and brain insulin resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, the goal of therapy should be to delay disease progression and eventual treatment failure. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. Optimal management should include early initiation of combination therapy using multiple drugs with different mechanisms of action. This review examines novel therapeutic options that hold particular promise.