The article discusses the critical role of early-life colonization by microbiota in shaping the immune system. During infancy, the immune system is highly influenced by the composition and diversity of the gut microbiota, which can have long-lasting effects on health and disease later in life. Recent studies have identified a critical period early in development when disruptions to optimal host-commensal interactions can lead to persistent or irreversible defects in immune subset development. The authors highlight the importance of this "window of opportunity" for proper immune education and resistance to disease. They review evidence from germ-free animal studies, which show that the absence of commensal microbes can lead to abnormalities in lymphoid tissue development, T cell subsets, B cells, innate lymphoid cells, and epithelial cells. The article also discusses the impact of early-life perturbations of the microbiota on human disease, including increased susceptibility to allergies, asthma, inflammatory bowel disease, and metabolic disorders. Finally, the authors emphasize the potential implications of these findings for preventing and treating complex diseases.The article discusses the critical role of early-life colonization by microbiota in shaping the immune system. During infancy, the immune system is highly influenced by the composition and diversity of the gut microbiota, which can have long-lasting effects on health and disease later in life. Recent studies have identified a critical period early in development when disruptions to optimal host-commensal interactions can lead to persistent or irreversible defects in immune subset development. The authors highlight the importance of this "window of opportunity" for proper immune education and resistance to disease. They review evidence from germ-free animal studies, which show that the absence of commensal microbes can lead to abnormalities in lymphoid tissue development, T cell subsets, B cells, innate lymphoid cells, and epithelial cells. The article also discusses the impact of early-life perturbations of the microbiota on human disease, including increased susceptibility to allergies, asthma, inflammatory bowel disease, and metabolic disorders. Finally, the authors emphasize the potential implications of these findings for preventing and treating complex diseases.