Semaphorins, a family of genes encoding guidance molecules in the nervous system, influence a variety of cellular mechanisms including migration, proliferation and cytoskeleton reorganization. Interestingly, many members are expressed throughout lymphoid tissues and by different immune cells like lymphocytes, NK, monocytes and dendritic cells. Besides, the array of functions semaphorins usually regulate during organogenesis coincide with several key events required for the initiation as well as the regulation of the host immune response. Thus, it is not surprising if a substantial number of them modulates immune processes such as the establishment of the immunological synapse, differentiation to effector and helper cells, clonal expansion, migration and phagocytosis. For this purpose, immune semaphorins can signal via their canonical plexin receptors but also possibly by unique discrete cell surface proteins or associations thereof expressed by, and critical to, leukocytes. A growing list of semaphorins, receptors or related molecules keep being reported in the immune system, and display nonredundant roles at controlling its integrity and efficacy.