Thiazolidinediones (glitazones) are the only compounds currently available that specifically target tissue insulin resistance. The two currently available drugs in this class, pioglitazone and rosiglitazone,are approved by the Food and Drug Administration for the treatment of type 2 diabetes mellitus only. The therapeutic potential of the glitazones for other consequences of insulin resistance has stirred considerable interest, especially with regard to their potential beneficial impact on atherosclerotic cardiovascular disease and diabetes prevention. They also have been considered in the management of polycystic ovarian syndrome, nonalcoholic fatty liver disease, and other consequences of insulin resistance. The nonglycemic potential of glitazones is a clinical area in rapid evolution, wherein most data are on the impact of the glitazones onsurrogate markers that are associated with diseases, not on disease outcomes. This article provides insight and guidance to clinicians on the diverse nonglycemic potential of glitazones until conclusive outcome data become available.