Recently, the role of the microbiome for health and disease has received significant attention. The microbiome development in the first weeks of life is highly dynamic and provides a window of opportunity, particularly for susceptible infants such as extremely preterm babies. The "healthy" microbiome implies a symbiotic life of the host with "friendly" microbes, which provides metabolic homeostasis and protection from invasive infection and sustained inflammation. It seems obvious that newborn infants are sensitive to microbiome-disturbing factors which can cause dysbiosis - an imbalance with reduced microbial diversity and deficient metabolic capacity to control potential pathogens ("foes"). Presumably, gut dysbiosis may contribute to adverse short-term outcome (e.g., sepsis and necrotizing enterocolitis) but may also be associated with long-term health problems such as asthma, growth failure, or neurodevelopmental deficits. In this review, we present the latest insights into our understanding on the physiological development of the microbiome and its interaction with the host. We will discuss the role of the microbiome in neonatal disease states and the potential of modifications advantageous to the susceptible newborn.