In recent years, the thiazolidinediones (e.g. rosiglitazone, pioglitazone) have emerged as an exciting novel class of therapeutic agent for the treatment of type 2 diabetes mellitus and the human metabolic syndrome. At first glance, the use of these high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, that promote adipogenesis, to treat a group of disorders that typically have their origins in obesity seems counter-intuitive. However, to view PPARgamma simply as a regulator of fat mass, and adipocytes themselves as passive vessels for energy storage, is to ignore an extensive body of data that speaks of the diverse roles of both this receptor and adipose tissue in the maintenance of normal metabolic homeostasis. This article highlights the important clinical and laboratory observations made in human subjects harbouring genetic variations in PPARgamma that have confirmed its pivotal role in the regulation of adipocyte endocrine function, and thus our metabolic response to the environment.