Substitute feedings have been used to treat infants with cow milk protein allergy for most of this century. For the past 50 years, several infant formulas based on animal proteins, both intact and chemically modified, or on vegetable protein have been labeled "hypoallergenic." Because of the risk of anaphylaxis and other serious adverse reactions, formulas that are claimed to be hypoallergenic should be subjected to rigorous preclinical and clinical testing. At a minimum, such formulas should not provoke any allergic signs or symptoms in 90% of infants with documented cow milk protein allergy when tested in double-blind, placebo-controlled trials. A standardized definition of "hypoallergenic" will allow clinicians and parents to understand the true risks to a cow milk-allergic infant fed such hypoallergenic formulas.