The purpose of this review is to present our approach to diagnosis of the child with liver disease. Since liver disease is relatively rare in pediatric practice, most clinicians lack experience with its diagnosis. Furthermore, diverse disorders can present with virtually identical findings because liver injury expresses itself in limited ways, particularly in the neonate. However, within the limited patterns of presentation, there is usually sufficient diversity to allow for discrimination and, therefore, differential diagnosis. Clinicians can use pragmatism and logic to achieve a systematic and practical approach to diagnosis. This approach uses a matrix that combines several simple parameters-the age at presentation, the dominant presenting findings, and a few well-chosen tests-to arrive at a very limited differential. From that point, specific, focused investigations can confirm the diagnosis.