Epidemiological data suggests that early life exposures are key determinants of immune mediated disease later in life. Young children are also susceptible to infections, warranting more analyses of immune system development early in life. Such analyses have mostly been performed in mouse models or human cord blood samples, but these cannot account for the complex environmental exposures influencing human newborns after birth. We have performed a systems-level analysis of newborn immune system development and uncovered drastic developmental changes, triggered by environmental exposures, and following a shared stereotypic pattern. Here I will describe our latest results in our pursuit of understanding how early-life environmental exposures shape human immune systems, how tolerance to colonizing microbes is established and the functional capacity and infectious disease susceptibility is determined in human newborns.