Cholestatic and bile duct diseases affecting pediatric patient, particularly neonatal cholestasis, encompasses a unique group of conditions, and like other liver conditions a practical approach is needed when evaluating these cases. As with many liver conditions, but especially in this unique group, an understanding of the clinical findings is crucial, as many of the histologic findings are nonspecific, but in the proper clinical setting and laboratory findings, the pathologists can provide a narrower differential diagnosis based on the histologic findings. For example, a biopsy from a patient with neonatal cholestasis with a giant cell hepatitis pattern, but a low/normal γ-glutamyl transferase, will put bile acid synthesis defect disorder and progressive familial intrahepatic cholestasis among the top differential diagnoses.