The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play crucial roles in metabolic diseases such as hyperlipidemia, insulin resistance, and diabetes. The three PPAR subtypes, alpha, gamma, and delta, have distinct expression patterns and regulate glucose homeostasis based on the need of a specific tissue. While PPARalpha potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates, PPARgamma is essential for adipocyte differentiation and hypertrophy, and mediates the activity of the insulin sensitizing thiazolidinediones. PPARdelta may be important in regulating body weight and lipid metabolism in fat tissues. Thus, uncovering the regulatory mechanisms and transcriptional targets of these PPARs will provide insights into the pathogenesis of metabolic diseases and offer valuable information for rational drug design.