Metabolic disorders are disruptions in nutrient metabolism or basic cellular processes that can result in severe neonatal crisis. Basic laboratory findings may reveal hypoglycemia, acidosis, or hyperammonemia, but may also be normal even in infants with severe metabolic decompensation. Breast milk or milk-based formulas often contain the nutrient that precipitates the metabolic crisis and may need to be held during acute illness. Instead, infants with suspected metabolic disorders should be administered a high glucose infusion rate with isotonic fluids to reverse catabolism. Combined advanced biochemical and molecular testing is often needed to identify specific metabolic disorders and guide ongoing treatment.