Atherosclerosis is a chronic inflammatory vascular disease with complicated pathogenesis involving multiple cells and molecules. Semaphorin is a family of secreted, transmembrane, and GPI-anchored axon signaling proteins that play an important role in many pathophysiological processes by binding to their receptors neuropilin and plexin, such as nerve growth, immune response, tumor metastasis, angiogenesis, and metabolic disease. Studies on the cellular and molecular mechanisms of semaphorin in atherosclerosis have been progressed in the past decade. This article summarizes the research progress on the role of semaphorin in the development of atherosclerosis, focusing on how semaphorin affect vascular cells and blood cells, and regulate angiogenesis.