The metabolic activity of the liver plays a central role in coordinating the supply of energy to peripheral organs, in particular the brain. It is at the heart of an adaptive system, which allows survival at times of food deprivation and governs the storage of excess energy when plenty of food is available. The liver controls the storage of energy first by converting glucose into glycogen and, second, by esterifying excess fatty acids (FA) to triacylglycerol, which is released as a component of the very low density lipoproteins (VLDL), finally to be stored in the form of triglycerides (TG) mainly in the adipose tissue. Conversely, during starvation, when plasma glycerol and free FA (FFA) levels are high due to TG lipolysis in the adipose tissue, the liver FA oxidative machinery participates in the production and release of ketone bodies that serve as lipid-derived fuel for the brain, muscle, kidney and other peripheral organs. Furthermore, plasma glucose levels are maintained by the depletion of the hepatic glycogen stores and then by de novo glucose synthesis. A dysfunction of the fine tuning of these metabolic pathways participates in ailments that affect millions of people, which are collectively known as metabolic syndrome. It is now well established that elevated circulating FFA levels, as seen in obesity, promote type 2 diabetes in part by stimulating hepatic gluconeogenesis and glucose output into the bloodstream. During the past decade, it has been recognized that FAs are potent modulators of gene expression via the transcription factors peroxisome proliferator activated receptors (PPARs). These receptors have been identified as key regulators of energy homeostasis when activated by FAs or FA derivatives that bind to them. Therefore, it is not surprising that synthetic PPAR ligands are used as drugs to treat metabolic disorders. Although the action of PPARs is obviously not limited to the liver, herein we will focus on their major hepatic effects in health and disease.