Lipid mediators have complex effects on the cell; one of the key transcriptional factors that moderate proliferation and inflammatory effects is PPARβ/δ. Following highly successful clinical trials using the PPARβ/δ agonists GW501516 for treatment of diabetes, GSK announced that any further research would be discontinued due to preclinical trials in rodents which linked this drug to wide spread tumour development. In this review we outline the dual molecular functions of PPARβ/δ and connect these to the diverse results from in vitro studies, and draw parallels with the outcomes of animal and human studies. The PPARβ/δ agonists have a great potential in terms of therapy, and we hope to provide some insight into the reasons why such contrasting results have been published. The discussion presented here is important to the future development of PPARβ/δ agonists for the clinic, and for a fuller understanding for their complex regulatory roles in the cell.