Peroxisome proliferators (PPs) have been shown to regulate hepatic lipid metabolism via activation of the peroxisome proliferator-activated receptor alpha (PPAR-alpha). Recent studies have revealed that PPs also exert considerable influence on certain extrahepatic tissues, including adipose tissue and lymphoid organs, in an indirect fashion. Inhibition of the proliferation of thymocytes and splenocytes and alteration of fatty acid uptake into and release from adipose tissue might be consequences of the hypolipidemic effect of PPs involving both PPARalpha-dependent and -independent pathways. Exposure to PPs reduces the cholesterol content of circulating low-density lipoprotein (LDL), which is the major supply of this steroid to most peripheral tissues. In addition, PPs increase serum levels of high-density lipoprotein (HDL), which extracts cholesterol from peripheral tissues and returns it to the liver, thereby further decreasing the cholesterol content of peripheral tissues. This net flux of cholesterol from extrahepatic tissues to the liver represents a change in global lipid homeostasis. In normal healthy young mice, this hypolipidemic effect could result in loss of cholesterol and other lipids from peripheral tissues (e.g., adipose tissue, thymus, and spleen), especially from plasma membrane caveolae, which might perturb normal cellular signaling and result in tissue atrophy. On the other hand, the increased hepatic cholesterol content in the hepatocyte plasma membrane might actually enhance signaling, playing a role in the liver hypertrophy and hepatocarcinogenecally associated with long-term PP treatment. In conclusion, it is important to consider the systemic effects of PPs, rather than to focus on the liver alone.