More than 75 years ago, Schoenheimer reported that mammals not only synthesize cholesterol de novo, but also selectively absorb dietary cholesterol from the small intestine while excluding dietary plant sterols and other noncholesterol sterols (1). Subsequent studies have built on this work, demonstrating that cholesterol homeostasis depends on a balance between de novo cholesterol synthesis, the absorption of dietary cholesterol, and excretion of excess cholesterol via the hepatobiliary system. Although cholesterol synthesis and breakdown pathways are well defined, the pathway of dietary cholesterol absorption remains to be elucidated. We still need mechanistic insights to explain Schoenheimer’s observations of selective sterol absorption—that is, the absorption of cholesterol but not plant sterols by intestinal epithelial cells (enterocytes). Given the link between plasma cholesterol levels and heart disease, the mechanism of dietary cholesterol absorption is of great interest (2). Some knowledge has been gained by investigating cellular processes as disparate as vesicular transport, molecular chaperones in the endoplasmic reticulum, lipid-transfer proteins, sterol-esterification enzymes, and rare genetic disorders (see the figure). The pharmaceutical industry is actively seeking drugs that specifically inhibit cholesterol absorption without affecting the absorption of other dietary lipids. The discovery of the drug ezetimibe (Zetia)—which specifically blocks intestinal cholesterol absorption by binding to a protein on the apical surface of enterocytes—has garnered much interest. Elucidating the target protein of ezetimibe may reveal the identity of a putative cholesterol transporter. On page 1201 of this issue, Altmann et al.(3) report the discovery of a protein that has the characteristics of a cholesterol transporter, perhaps bringing the search for this elusive protein to a close. Given that ezetimibe specifically blocks cholesterol absorption, Altmann and colleagues reasoned that its target must have the structural characteristics of a cholesterol transporter. They searched human and rodent expressed sequence tag (EST) databases for protein sequences that are highly expressed in the intestine and that contain characteristic features of transporters (transmembrane domains, an extracellular signal peptide, and N-linked glycosylation sites). But, crucially, they also sought proteins containing a “sterol-sensing” domain as found in other proteins known to interface with cholesterol, such as Neimann-Pick C1 (NPC1), HMG CoA reductase, and the Patched receptor. They identified a single rodent protein with these features and discovered that it is homologous to human Niemann-Pick C1 Like 1 protein (NPC1L1, also known as NPC3). To test whether NPC1L1 is required for cholesterol absorption in vivo, they created a mouse deficient in the Npc1l1 gene. Absorp-