The semaphorin family members were originally considered to play a role in neurodevelopment, angiogenesis, tumor development, and metastasis. Over the past few years, a growing body of data indicates that semaphorins are involved in the regulation of the immune system, identified in this case as the "immune semaphorins." These semaphorins are involved in almost all phases of both normal and pathological immune responses and were demonstrated to participate in allergic diseases as well as in auto-immune pathologies. Some of them, such as semaphorin 3A (sema3A), is important in downregulating autoimmune diseases by suppressing the over-activity of both T and B cell autoimmunity. In addition, sema3A was shown to enhance the ability of T and B cell regulatory properties and by doing so to control autoimmune diseases, such as systemic lupus erythematosus. Other semaphorins, such as semaphorins 4D and 4A are important in stimulating T and B cells, thus keeping these immune responses on-going. However, when overexpressed, they can induce the induction of many immune-mediated diseases. The importance of all this is to develop targeting therapies that could possibly enhance or alternatively suppress these molecules. In this review, we will focus on several immune semaphorins--their role in immune homeostasis and in immune-mediated diseases.