Human milk contains numerous components that shape the microbial content of the developing infant gastrointestinal tract. Studies suggest a co-evolutionary relationship between mammalian milk glycans, infant-borne bifidobacteria and the infant host resulting in a programmed enrichment of a protective bifidobacterial-dominant community during a critical stage of infant development. Disruption of this programmed enrichment, by poor environmental transfer, antibiotic use, or infection, can lead to a “poorly functioning milk-oriented microbiota that may pose a risk for negative health outcomes. Further analysis of this naturally evolved system will shed light on effective pre- and probiotic tools that support and ensure a protective gut microbiota for at-risk infants.