Semaphorins were originally identified as axon-guidance molecules that function during neuronal development. However, cumulative evidence indicates that semaphorins also participate in immune responses, both physiological and pathological, and they are now considered to be potential diagnostic and/or therapeutic targets for a range of diseases. The primary receptors for semaphorins are neuropilins and plexins, which have cell type-specific patterns of expression and are involved in multiple signalling responses. In this Review, we focus on the roles of neuropilin 1 (NRP1) and plexins in the regulation of the immune system, and we summarize recent advances in our understanding of their pathological implications.