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Netrins and semaphorins, members of the neuronal guidance cue family, exhibit a rich biology with significant roles that extend beyond chemotactic guidance of the axons to build the neuronal patterns of the body. Screening of adult tissues and specific cellular subsets have illuminated that these proteins are also abundantly expressed under both steady state and pathological scenarios. This observation suggests that, in addition to their role in the development of the axonal tree, these proteins possess additional novel functions in adult physiopathology. Notably, a series of striking evidence has emerged in the literature describing their roles as potent regulators of both innate and adaptive immunity, providing extra dimension to our knowledge of neuronal guidance cues. In this review, we summarize the key complex roles of netrins and semaphorins outside the central nervous system (CNS) with focus on their immunomodulatory functions that impact pathophysiological conditions. [ABSTRACT FROM AUTHOR]