Cholesterol accumulation in the body is associated with disease, most prominently atherosclerosis.1 Cholesterol is either taken up from the diet or de novo synthesized in almost all body cells.1 It is essentially a metabolically inert molecule, the sterol nucleus cannot be degraded, and the only way to remove substantial amounts of cholesterol from the body is fecal excretion either directly or after conversion into bile acids.2 Fecal excretion can occur via 2 independent pathways. The first pathway is represented by biliary secretion, which has been extensively characterized and studied.3 The second pathway is cholesterol excretion by enterocytes, a mechanism that has gained considerable attention during the last 5 years. In 2007, the enteral route of cholesterol elimination from the body was coined as transintestinal cholesterol excretion (TICE; Figure).4 See accompanying article on page 1484 Initial studies estimated TICE to contribute ≈30% to total fecal neutral sterols excreted from the body in wild-type mice,5 which is quite a substantial part. This number is fueling the hope that, if accessible to therapeutic modulation, substantial amounts of cholesterol can be excreted via TICE from the body using drugs that would be predicted to only have minimal systemic side effects, because local action in the gut would seem sufficient. About regulation of TICE, thus far, high-fat diet,6 plant sterols,7 and liver X receptor activation5 as well as PPARδ ligands8 have been identified as activators. …