Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is a common condition with a worldwide distribution that has the potential for causing severe hyperbilirubinemia with bilirubin encephalopathy. Hemolysis resulting from identifiable triggers may be the cause of the jaundice in some cases, but in many, jaundice continues to occur despite avoidance of contact with known hemolytic triggers. In some G-6-PD-deficient population groups, carboxyhemoglobin studies have indicated exaggerated hemolysis; but in others, increased hemolysis has not correlated with serum total bilirubin values. As hyperbilirubinemia results from an imbalance between bilirubin production and bilirubin elimination, diminished bilirubin conjugation was suspected to contribute to the pathogenesis of hyperbilirubinemia. Serum-conjugated bilirubin fractions, reflecting intrahepatocytic bilirubin conjugation, were low in G-6-PD-deficient neonates who developed hyperbilirubinemia. This conjugated bilirubin profile was similar to that seen in adults with Gilbert's Syndrome, a condition associated with promoter polymorphism for the gene encoding the bilirubin-conjugating enzyme, UGT glucuronosyltransferase 1A1 (UGT). Whereas G-6-PD deficiency or Gilbert's Syndrome, alone, did not predispose to hyperbilirubinemia, G-6-PD-deficient neonates who also were heterozygotes or homozygotes for the variant UGT gene promoter did have significantly increased incidences of hyperbilirubinemia. Additional conditions which predispose to neonatal jaundice in the presence of Gilbert's Syndrome, include Coombs' negative ABO blood group heterospecificity, hereditary spherocytosis, and prolonged breastfeeding.Gilbert's Syndrome and G-6-PD deficiency are both common, inherited conditions. Individually, and in the absence of additional genetic or environmental factors, both are benign, and should result in minimal health disturbance or interference with the quality of life of affected individuals. However, in combination, or following exposure to environmental or other genetic factors, these benign conditions may have severe manifestations, with potentially dangerous and possibly life-threatening consequences. This review highlights the major clinical features of both Gilbert's Syndrome and G-6-PD deficiency, and surveys a series of studies related to neonatal jaundice in G-6-PD-deficient neonates culminating in the documentation of an interaction between the two conditions that is crucial to the pathogenesis of hyperbilirubinemia.