Parenteral nutrition-associated cholestasis is a major clinical problem in pediatrics, particularly during infancy in children with short bowel syndrome who require long-term use of total parenteral nutrition (TPN) for survival. Multifactorial theories regarding the origin of parenteral nutrition-associated cholestasis have not yet defined its pathogenesis or resulted in a solution to the problem. However, our knowledge of risk factors has helped develop new hypotheses as to the mechanisms of this disease. In this review, we consider the following potential risk factors that influence the development of this condition: (1) the gastrointestinal dysfunction associated with the absence of enteric nutrients while receiving TPN; (2) components of TPN solutions as potential hepatotoxins; and (3) the contribution of the underlying disease necessitating TPN for adequate nutrition. It is hoped that a better understanding of factors affecting hepatocyte secretion and bile formation and flow will help to prevent this life-threatening complication of TPN.