Exclusive breast-feeding is unambiguously the optimal infant feeding practice and is universally promoted in the absence of human immunodeficiency virus (HIV-1). It is associated with reduced morbidity and mortality from diarrheal and respiratory diseases. Recent findings suggest that exclusive breast-feeding may pose less risk of HIV-1 transmission than the more common practice of mixed feeding (i.e., breast-feeding concurrent with the feeding of water, other fluids, and foods), which has important infant feeding policy implications for low-resource settings. This paper reviews the biologic mechanisms associated with exclusive breast-feeding that provide protection against gastrointestinal, respiratory, and atopic diseases, and evaluates the relevance of these mechanisms for HIV-1 transmission. Potential mechanisms include reduction in dietary antigens and enteric pathogens that may maintain integrity of the intestinal mucosal barrier and limit inflammatory responses of the gut mucosa; promotion of beneficial intestinal microflora that may increase resistance to infection and modulate the infant's immune response; alteration in specific antiviral or anti-inflammatory factors in human milk that may modulate maternal hormonal or immunologic status; and maintenance of mammary epithelial integrity that may reduce viral load in breast milk.