Initiating and advancing insulin therapy in patients with type 2 diabetes mellitus can be challenging. However, with the availability of insulin analogs with more physiologic profiles, and with the initiation of simple insulin regimens (eg, the use of basal insulin administered once daily), an opportunity is created to empower patients to self-titrate their insulin. Self-titration can reduce the burden on the physician as well as improve glycemic control in patients. More options for intensifying insulin now exist, including gradually adding prandial insulin (referred to as a basal "plus" strategy) or using premixed insulin analogs for patients with relatively consistent lifestyles and habits. More-concentrated forms of insulin, such as U-500 insulin, may be helpful for patients requiring very large doses of insulin. The key is to match the insulin regimen to the patient; engage in dialogue to understand the patient's lifestyle, concerns, and skill sets; and develop, through a shared decision-making process, appropriate individualized treatment recommendations. The present review article focuses on the use of insulin replacement therapy in challenging patient cases.