Liver steatosis (increased hepatocyte accumulation of triglycerides) and cholesterol gallstones (precipitation of solid cholesterol from supersaturated gallbladder bile) are lipidopathies associated with the emerging metabolic syndrome in cultures consuming a "Western" diet (consisting of high total calories, cholesterol, saturated fatty acids, refined carbohydrates, proteins, and salt, as well as low fibers). The small intestine is a unique organ providing dietary and re-absorbed biliary cholesterol to the body, and also fatty acids, essential component of triglycerides. Interestingly, the cholesterol absorption inhibitor ezetimibe (EZT) can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter. Unexpectedly, EZT treatment induced a complete resistance to cholesterol gallstones and fatty liver disease besides hypercholesterolemia in mice on a Western diet. Since chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acid into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases mostly through manipulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. Understanding the molecular mechanisms governing the intestinal-hepatic cross-talk through the chylomicron pathway, could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and liver steatosis.