Intestinal failure (IF) is the ultimate malabsorption state, with multiple causes, requiring long-term therapy with enteral or intravenous fluids and nutrient supplements. The primary goal during management of children with potentially reversible IF is to promote intestinal autonomy while supporting normal growth, nutrient status, and preventing complications from parenteral nutrition therapy. This article presents how an improved understanding of digestive pathophysiology is essential for diagnosis, successful management, and prevention of nutrient deficiencies in children with IF.