Recent advances in bile-salt research have revolutionized thought pertaining to the regulation of cholesterol homeostasis by highlighting the molecular control of reverse cholesterol transport and cholesterol catabolism to bile acids. The latter involves both feed-forward and feedback regulation of bile-acid synthesis within the territory of the enterohepatic circulation of bile salts. Cholesterol is vital to advanced life forms because it has become essential for membrane structure and function and is a precursor to the synthesis of steroid hormones, vitamins A and D, and bile acids. The liver plays a major part in cholesterol metabolism in that it is capable of de novo cholesterol synthesis and uptake from high-density lipoprotein reverse cholesterol transport, low-density lipoprotein, and chylomicron remnant receptors, so that 50% of total body cholesterol is available to be catabolized to bile acids. Cholesterol catabolism to bile acids allows the eukaryote cell to maintain cholesterol homeostasis because it cannot degrade cholesterol’s cyclopentanoperhydrophenanthrene ring. Bile-salt catabolic end products of cholesterol must also be regulated to maintain normal bile-acid pool size, secretion, and elimination to avoid bile-salt hepatocyte toxicity. Nuclear hormone receptors, after sensing inappropriate oxysterol and bile-salt levels, are transcription factors that initiate the genetic transactivation to modulate reverse cholesterol transport, cholesterol catabolism, and bile-acid metabolism contiguous to and within the enterohepatic circulation of bile salts so as to regulate cholesterol and bile-salt homeostasis, respectively. This new knowledge should spawn pharmacologic discoveries that modulate nuclear receptors for the treatment of disorders of cholesterol homeostasis.