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The Semaphorin family is a group of proteins studied broadly for their functions in nervous systems. They consist of eight subfamilies ubiquitously expressed in vertebrates, invertebrates, and viruses and exist in membrane-bound or secreted forms. Emerging evidence indicates the relevance of semaphorins outside the nervous system, including angiogenesis, cardiogenesis, osteoclastogenesis, tumour progression, and, more recently, the immune system. This review provides a broad overview of current knowledge on the role of semaphorins in the immune system, particularly its involvement in inflammatory and infectious diseases, including chlamydial infections.