Type 2 diabetes mellitus is a progressive disorder, and maintenance of near-normal glycemic control has been demonstrated to reduce the risk of its associated long-term vascular complications. This treatment goal can be achieved in most patients with use of single oral agents, combinations of oral agents, or insulin. Secondary failure rates for intensive oral or injected therapy are high, however, especially in patients with long-standing disease. A substantial body of evidence indicates that combination therapy with insulin and oral antidiabetic agents can safely establish excellent glycemic control in most patients, while it reduces the required dosage of insulin and, in some combinations, mitigates the weight gain associated with insulin therapy. The availability of more convenient insulin-delivery systems may render the addition of insulin to oral drug therapy more acceptable to patients and clinicians. The most-studied combination is that of insulin and the sulfonylurea drugs. Randomized, prospective clinical trials have documented the benefits of thiazolidinediones, metformin, and acarbose in combination with insulin. To date, however, clinical trial data are insufficient for use in determining the optimal combination of agents, insulin formulations, and dosages among the many currently available possibilities.