Abstract: Semaphorin 4D (SEMA4D), also known as CD100, is a protein that belongs to class IV semaphorin. Its physiologic role in the nervous system has been extensively explored. However, the roles of SEMA 4D have extended beyond the traditionally studied territories. Collective data proved that SEMA 4D has an important role in the regulation of immune system, angiogenesis, and tumorigenesis, among others. Specifically, SEMA 4D enhanced the angiogenesis in malignant diseases. This review summarized the latest progression in the research on SEMA 4D, including the structure, receptors, mechanism, and biological functions in tumor angiogenesis and progression.