Molecules from symbiotic microorganisms pervasively infiltrate almost every organ system of a mammalian host, marking the initiation of microbial-host mutualism in utero, long before the newborn acquires its own microbiota. Starting from in utero development, when maternal microbial molecules can penetrate the placental barrier, we follow the different phases of adaptation through the life events of birth, lactation, and weaning, as the young mammal adapts to the microbes that colonize its body surfaces. The vulnerability of early-life mammals is mitigated by maternal detoxification and excretion mechanisms, the protective effects of maternal milk, and modulation of neonatal receptor systems. Host adaptations to microbial exposure during specific developmental windows are critical to ensure organ function for development, growth, and immunity.