Cholestasis, defined as a reduction of bile flow, may be secondary to obstruction of bile ducts or absence of production of bile by hepatocytes. Genetic hepatocellular cholestasis is a heterogenous group of diseases, including bile acid synthesis defects (BASD) and progressive familial intrahepatic cholestasis (PFIC). It affects a gene involved in either bile acid synthesis (BASD) or bile secretion by hepatocytes (PFIC). Recent advances in molecular biology and sequencing techniques have enabled the identification of many novel cholestatic disorders beyond the three historical PFIC. These diseases, of variable severity, are responsible for chronic cholestasis, intractable pruritus and often progress toward early liver cirrhosis, liver failure and liver cancer. Novel therapeutics such as ileal bile acid transporter inhibitors have been developed for the treatment of pruritus. Many patients with genetic hepatocellular cholestasis will require liver transplantation during childhood because of intractable pruritus or worsening of liver function. Specific subsets of BASD manifesting as chronic cholestasis are treatable with primary bile acid therapy with excellent native liver survival in the long-term. In this publication, we will review the clinical, biochemical and molecular features of genetic hepatocellular cholestasis, as well as their management.