Cholestasis results from structural and functional impairment of the hepatobiliary system, which is often the target of several environmental factors and disease processes. This review focuses on the clinical consequences of this impairment. When evaluating an infant or child with cholestasis, a broad differential diagnosis must be considered; viral infections, metabolic disorders, and toxic insults may often lead to cholestasis. In the infant, cholestasis associated with severe hepatic synthetic dysfunction points to life-threatening metabolic disorders. In this setting, early diagnosis and prompt treatment offer the only chance for survival. Fortunately, cholestasis in infants presents more frequently with initially normal liver synthetic function. In those infants without evidence of infection, evaluation for patency of the extra-hepatic biliary system is a high priority. Biliary atresia comprises a significant portion of these patients and requires surgical intervention with portoenterostomy in an attempt to improve biliary flow. In a substantial group of infants and older children in whom the cause for cholestasis is not apparent, typical clinical and biochemical markers may allow the identification of specific genetic defects of syndromes that result from abnormal canalicular transporters.