Liver X receptors (LXRs) alpha and ss belong to a family of nuclear receptors which form heterodimers with the retinoid X receptor and, upon ligand binding, stimulate the expression of target genes. LXRs were initially described as orphan receptors and oxidized cholesterol derivatives (oxysterols) were later identified as their natural ligands. In addition, several synthetic LXR agonists such as T0901317 and GW3965 were synthesized. Oxysterols are formed in amounts proportional to cholesterol content in the cell and therefore the LXRs operate as cholesterol sensors which protect from cholesterol overload by: 1) inhibiting intestinal cholesterol absorption, 2) stimulating cholesterol efflux from cells to high-density lipoproteins through the ATP-binding cassette transporters ABCA1 and ABCG1, 3) activating the conversion of cholesterol to bile acids in the liver, and (4) activating biliary cholesterol and bile acid excretion. In addition, LXR agonists activate de novo fatty acid synthesis by stimulating the expression of a lipogenic transcription factor, sterol regulatory element-binding protein-1c (SREBP-1c), leading to the elevation of plasma triglycerides and liver steatosis. Here we describe the structure and function of the LXRs, their endo- and exogenous agonists and antagonists, the regulation of LXR expression and activity, and their role in the regulation of cholesterol and lipid metabolism. In the accompanying article we characterize other effects of LXRs, alterations in LXR expression, and changes in the level of their endogenous agonists in pathological conditions as well as therapeutic implications.