The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro–immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.