The enterohepatic circulation of bile acids (BAs) is governed by specific transporters expressed in the liver and the intestine and plays a critical role in the digestion of fats and oils. During this process, the majority of the BAs secreted from the liver is reabsorbed in intestinal epithelial cells via the apical sodium-dependent bile acid transporter (ASBT/SLC10A2) and then transported into the portal vein. Previous studies revealed that regulation of the ASBT involves BAs and cholesterol. In addition, abnormal ASBT expression and function might lead to some diseases associated with disorders in the enterohepatic circulation of BAs and cholesterol homeostasis, such as diarrhoea and gallstones. However, decreasing cholesterol or BAs by partly inhibiting ASBT-mediated transport might be used for treatments of hypercholesterolemia, cholestasis and diabetes. This review mainly discusses the regulation of the ASBT by BAs and cholesterol and its relevance to diseases and treatment.