Background <p>Immune cells seed tissues in orchestrated waves beginning in utero. While the impact of prenatal environmental exposures is well-documented in neuroimmunology, the influence of maternal-fetal interactions on systemic immune development and its contribution to lifelong chronic inflammatory disease remains underappreciated.</p> Main body <p>This narrative review synthesizes recent ontogeny data to demonstrate how diverse prenatal cues, ranging from maternal infection to microbial-derived metabolites, function as a “prenatal training ground” for the developing fetal immune system. These maternal signals interact with specific waves of hematopoiesis to shape long-lived tissue-resident immune cells. In many tissues, these prenatally programmed populations persist into adulthood, acting as lifelong immunological rheostats that dictate the type and intensity of local inflammatory responses. Furthermore, we critically evaluate the translational gaps in the field, highlighting fundamental species-specific differences in developmental timelines that necessitate careful alignment between preclinical animal models and human biology.</p> Conclusions <p>We propose that many chronic immune conditions are not strictly adult-onset in their etiology, but rather adult-manifesting, making prenatal immune seeding a critical, yet overlooked, determinant of long-term health. Current interventions largely focus postnatally, but reorienting research and clinical focus toward prenatal factors provides new insights into the developmental origins of chronic inflammation and offers a novel therapeutic window to optimize the health trajectory of the next generation.</p>