The liver is considered the major “control center” for maintenance of whole-body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis, clearing cholesterol-containing chylomicron remnants and low-density lipoprotein (LDL) particles from plasma and is the major contributor to high-density lipoprotein (HDL) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up periphery-derived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ: selective modulation of this process may provide an effective means to accelerate cholesterol turnover. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels and that intestine-specific activation of LXR leads to “clinically relevant” elevation of plasma HDL levels in animal models. Thus, the intestine is a potential target for novel anti-atherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.