The ability to improve insulin sensitivity with synthetic compounds was uncovered by empirical discoveries by Takeda in the late 1970s. The potential of a class of thiazolidinediones for the treatment of Type 2 diabetes, by decreasing glucose and triglycerides alongside lowering circulating insulin, was made public during the 1980s. As the first of the chemicals (pioglitazone, troglitazone and rosliglitazone) proceeded to clinical trials, these observations were soon extended to demonstrate a rich and complex pharmacology. The promise of this mode of action included prevention of diabetes as well as making a significant impact on the incidence and severity of the life-shortening consequences of the established disease. There are now two of these drugs on the market: pioglitazone and rosiglitazone, and they are being used to treat significant numbers of diabetic patients. However, the use of these drugs and development of future generations of successful candidates has not met the expectations that were held out in the early 1980s. This can be attributed to two major prevailing conditions. Troglitazone became the first thiazolidinedione to be approved as a result of delays in the development of pioglitazone. Unfortunately, troglitazone produced a unique idiosyncratic and sometimes fatal, hepatoxicity that necessitated its removal from the marketplace; second, there has been an incomplete understanding of the biochemical mechanism of action of these drugs that has slowed (and perhaps derailed) attempts to produce second-generation compounds. The latter issue is the subject of this editorial, which suggests that it is time to take a fresh look at the pharmacology of insulin sensitisers.