ABCB4 encodes a canalicular phospholipid transporter essential for biliary health. As an ATP-dependent floppase, ABCB4 translocates phosphatidylcholine from the inner to outer leaflet of the hepatocyte canalicular membrane into bile 1, making phospholipids available for extraction by bile salt mixed micelles 2. This translocation protects the biliary tree from the detergent toxicity of bile salts 1. ABCB4 also contributes to cholesterol efflux and regulates membrane lipid organization in hepatocytes 1. ABCB4 deficiency causes a spectrum of cholestatic and cholelithiasic diseases depending on mutational burden and inheritance pattern 1. Homozygous or compound heterozygous mutations cause progressive familial intrahepatic cholestasis type 3 (PFIC3), a severe pediatric disease characterized by low biliary phospholipids and high cholesterol saturation 3. Monoallelic variants predispose to low-phospholipid-associated cholelithiasis (LPAC)—early-onset gallstone disease with intrahepatic lithiasis and post-cholecystectomy recurrence—and intrahepatic cholestasis of pregnancy 4, 5. Adult-onset disease presentations include chr7 liver disease, biliary fibrosis, and cirrhosis 6. Most ABCB4-deficient patients respond to ursodeoxycholic acid therapy, though severe PFIC3 cases may require liver transplantation 3. Emerging evidence links ABCB4 variants to hepatobiliary malignancies 1.