The therapeutic goals in patients with type 2 diabetes mellitus and the mechanisms of insulin resistance and secretion are discussed. Sulfonylureas improve glycemic control, restore the acute insulin response, and help improve beta-cell function in the short term. Meglitinides and phenylalanine derivatives and alpha-glucosidase inhibitors may be useful for elderly patients and others with normal fasting blood glucose levels and postprandial hyperglycemia, but they are less effective in achieving goal HbA1c levels in patients with marked fasting hyperglycemia. Metformin and thiazolidinediones act on hepatic, muscle, and adipose tissue through different mechanisms to improve glycemic control, beta-cell function, and the lipid profile. Thiazolidinediones have a greater impact on free fatty acids than metformin. They may have an additive effect with sulfonylureas, metformin, or insulin in improving glycemic control and the lipid profile. Many patients require combination therapy with one or more insulin sensitizers and an insulin secretagogue to achieve therapeutic goals. Insulin therapy should be initiated in patients in whom an HbA1c level less than 7.0% cannot be maintained with other therapies. This is vital in preventing diabetes complications. Insulin sensitizers should be continued during insulin therapy to reduce insulin resistance and treat the insulin resistance syndrome. Therapeutic goals for patients with type 2 diabetes mellitus include improvement in glycemic control and prevention of diabetes complications. Elevated levels of fasting blood glucose should be addressed before postprandial levels to reduce HbA1c levels and glucotoxicity to the beta cell. Dyslipidemia, hypertension, and hypercoagulability should be treated to minimize the increased cardiovascular risk seen in people with diabetes, which is responsible for the majority of deaths.