Atherosclerosis is the leading cause of illness and death. Therapeutic strategies aimed at reducing cholesterol plasma levels have shown efficacy in either reducing progression of atherosclerotic plaques and atherosclerosis-related mortality. The farnesoid-X-receptor (FXR) is a member of metabolic nuclear receptors (NRs) superfamily activated by bile acids. In entero-hepatic tissues, FXR functions as a bile acid sensor regulating bile acid synthesis, detoxification and excretion. In the liver FXR induces the expression of an atypical NR, the small heterodimer partner, which subsequently inhibits the activity of hepatocyte nuclear factor 4alpha repressing the transcription of cholesterol 7a-hydroxylase, the critical regulatory gene in bile acid synthesis. In the intestine FXR induces the release of fibroblast growth factor 15 (FGF15) (or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signalling to inhibit bile acid synthesis. In rodents, FXR activation decreases bile acid synthesis and lipogenesis and increases lipoprotein clearance, and regulates glucose homeostasis by reducing liver gluconeogenesis. FXR exerts counter-regulatory effects on macrophages, vascular smooth muscle cells and endothelial cells. FXR deficiency in mice results in a pro-atherogenetic lipoproteins profile and insulin resistance but FXR(-/-) mice fail to develop any detectable plaques on high-fat diet. Synthetic FXR agonists protect against development of aortic plaques formation in murine models characterized by pro-atherogenetic lipoprotein profile and accelerated atherosclerosis, but reduce HDL levels. Because human and mouse lipoprotein metabolism is modulated by different regulatory pathways the potential drawbacks of FXR ligands on HDL and bile acid synthesis need to addressed in relevant clinical settings.