The two thiazolidinediones (TZDs), pioglitazone (Actos) and rosiglitazone (Avandia), which are FDA approved for the treatment of type 2 diabetes mellitus (T2DM), have been fascinating drugs from the time of their development as agonists for peroxisomal proliferator-activated receptors (PPAR) of the gamma type. While it is clear from the registration trials and many other investigator-initiated trials that they are both insulin sensitizers as agents of efficacy to treat hyperglycemia, there has always been background “noise” (hyperbole) about their many other beneficial actions. The latter include beneficial effects on plasma lipid levels (at least for pioglitazone), blood pressure, inflammatory markers, and some coagulation parameters. There also appears to be an increase in subcutaneous, lower body fat with or without increases in intra-abdominal fat (although the role that these changes in adiposity has is not at all clear). In view of the potential benefit that these “beyond glucose” effects might have on cardiovascular risk, including the improvement in insulin resistance itself, there were great expectations for the TZDs as cardiovascular agents. However, several published reports during the last 2 years not only have reduced those expectations, but have caused some physicians and scientists to consider TZDs as potentially harmful drugs.