The semaphorin family is a large group of proteins controlling cell migration and axonal growth cone guidance. These proteins are bi-functional signals capable of growth promotion or growth inhibition. Initially described in the nervous system, the majority of studies related to semaphorins and semaphorin signalling are nowadays performed in model systems outside the nervous system. Here, we provide an exhaustive review of the many faces of semaphorins both during developmental, regulatory and pathological processes. Indeed, because of their crucial fundamental roles, the semaphorins and their receptors represent important targets for the development of drugs directed at a variety of diseases.