Bile acids (BAs) facilitate emulsification, absorption, and transport of fats and fat-soluble vitamins in the intestine and liver. Regulated by a complex process involving coordinated synthesis in the liver, transport from the liver to the intestine, and then back to the liver, when enterohepatic circulation is altered, accumulation of cytotoxic BAs can result in damage to hepatocytes as well as the intestinal epithelium. In experimental necrotizing enterocolitis (NEC), cholic acid (CA) and deoxycholic acid (DCA) are elevated in the intestinal lumen and correlate positively with disease incidence and severity. When BAs are pharmacologically sequestered in the ileum, incidence and severity of NEC are significantly decreased. Elevation of both ileal luminal and intra-enterocyte BAs precedes damage to the ileal architecture and infiltration of macrophages during development of NEC. Data also suggest BAs play a role in decreased mucin 2 (MUC2) observed in NEC. Accumulation of toxic BAs is thought to occur due to alterations in transporters involved in enterohepatic circulation of BAs, including the apical sodium-dependent bile acid transporter (ASBT), ileal bile acid binding protein (IBABP), heteromeric organic solute transporter (OSTα-OSTβ), bile salt excretory pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and sodium-dependent taurocholate-transporting polypeptide (NTCP). Neutralization of tumor necrosis factor (TNF-α) and interleukin IL-18 (IL-18), normalized NTCP and MRP2, respectively. In human NEC, ASBT is significantly increased on the apical membrane of enterocytes and total unconjugated fecal BAs levels are elevated.