Before initiating insulin therapy, clinicians often wait until oral antidiabetic agents fail to adequately reduce glycosylated hemoglobin (A1C) levels and control hyperglycemia in patients with type 2 diabetes. Long-term, randomized clinical trials demonstrate that reducing A1C to close to normal decreases rates of microvascular complications and can also reduce macrovascular complications. Insulin regimens that treat to target A1C levels may achieve greater control of hyperglycemia. Various randomized trials have assessed the efficacy and safety of initiating insulin therapy with human insulins and insulin analogs in patients with type 2 diabetes whose condition is inadequately controlled with oral antidiabetics. These studies assessed different regimens, including basal and premixed insulins, for their ability to reach target A1C goals and provided evidence-based protocols for the initiation and systematic dosage titration of insulin therapy in patients with type 2 diabetes. Examples of how to initiate and intensify insulin therapy to achieve target A1C goals based on these protocols are presented.