Hyperbilirubinemia is the most common condition requiring evaluation and treatment in neonates. Identifying among all newborns those few at risk to develop marked hyperbilirubinemia is a clinical challenge. Clinical, epidemiologic, and genetic risk factors associated with severe hyperbilirubinemia include late preterm gestational age, exclusive breastfeeding, glucose-6-phosphate dehydrogenase deficiency, ABO hemolytic disease, East Asian ethnicity, jaundice observed in the first 24 hours of life, cephalohematoma or significant bruising, and history of a previous sibling treated with phototherapy. It is increasingly apparent that the etiopathogenesis of severe hyperbilirubinemia is often multifactorial, and emerging evidence suggests that combining risk factor assessment with measurement of predischarge total serum or transcutaneous bilirubin levels will improve hyperbilirubinemia risk prediction.