This paper summarizes the important contributions that humangenetic studies have made to our understanding of the role ofPPARγ in the regulation of mammalian metabolichomeostasis, emphasizing the potential benefits and limitationsthat we can expect from more targeted approaches to modulatingreceptor function, and thus ensuring that in an era marked by anincreasing prevalence of obesity, diabetes and cardiovasculardisease, PPARγ remains more of “a help” than “ahindrance.” Here, PPARG is linked to diabetes mellitus.