Treatment options for type 2 diabetes mellitus currently consist of insulin. sensitizers, alpha-glucosidase inhibitors, secretagogues, and insulin. However, the emphasis on initial therapy has been shifting from secretagogues and alpha-glucosidase inhibitors to insulin sensitizers such as metformin and the thiazolidinediones (TZDs). This article outlines the benefits of treatment with sensitizers vis a vis alpha-glucosidase inhibitors and secretagogues as part of a comprehensive treatment algorithm for type 2 diabetes. Secretagogues and a-glucosidase inhibitors effectively lower plasma glucose levels only, whereas insulin sensitizers reduce several important cardiac risk factors in addition to reducing plasma glucose levels. TZDs, in particular, are also beneficial for their ability to preserve or even rejuvenate pancreatic beta-cell function. The treatment algorithm has a layered approach, beginning with a combination of insulin-sensitizer therapy and incrementally progressing to triple oral therapy with the addition of secretagogues and, if necessary, the addition of subcutaneous insulin to maintain glycemic control.