The current paradigm for pharmacologic management of type 2 diabetes mellitus (DM) is to progress with oral agents until severe insulin deficiency develops, at which time insulin can be initiated. Reexamination of data from the Diabetes Control and Complications Trial (DCCT) suggests that glycemic variability may be an important factor involved in the pathogenesis of microvascular complications. It is now appreciated that oxidative stress from overproduction of reactive oxygen species may be the result of this glycemic variability, suggesting that an overemphasis of basal insulin may not be the ideal strategy for insulin replacement, even though basal insulin is often the only insulin used initially. Although finding the best insulin program for treatment of type 2 DM is an important area of research, almost all patients with severe insulin deficiency will require both basal and prandial replacement. Use of adequate lag times (time between injecting the prandial insulin and eating), U-500 insulin (500 U/mL human regular insulin), and home blood glucose monitoring to determine “glycemic trend” are important tools that are readily available to all patients.