In addition to well-recognized antimicrobial substances, a growing body of evidence has accrued during the last decade regarding the presence and function of immunomodulatory and anti-inflammatory factors present in human milk and their role in protecting the mature newborn as well as the premature infant against infections. In addition, it is now appreciated that a number of these factors present in human milk may actively modulate the synthesis and maturation of the recipient immune system. This complex and interactive system of bioactive substances in human milk appears ideally to be designed to function by noninflammatory mechanisms, to operate often in a complementary or synergistic manner, to resist the digestive process in the recipient gastrointestinal tract, and to supplement developmentally delayed immune factors of the infant. The in vivo fate and effects of these immune factors in human milk, however, are still poorly understood. Clinical studies in conjunction with a broader use of experimental animal models and basic research are needed in the future to address these questions.