Several decades ago, fibrates were approved for the treatment of dyslipidemia, whereas thiazolidinediones were screened in animal models to improve glucose homeostasis and were subsequently developed for the treatment of type 2 diabetes mellitus. Relatively recently, these drugs were found to act via peroxisome proliferator-activated receptors, nuclear receptors that control lipid metabolism and glucose homeostasis. In this historical perspective, we discuss the history of discovery of the peroxisome proliferator-activated receptors, from the clinical development of their agonists to the subsequent discovery of these receptors and their mechanisms of action, to finally evoke possibilities of targeted pharmacology for future development of selective peroxisome proliferator-activated receptor modulators.