Atherosclerosis (As) is one of the major causes of high mortality and morbidity worldwide. Chemokines and their receptors are involved in the pathogenesis of As. CXC chemokine ligand 12 (CXCL12) is a member of the chemokine family, and macrophage migration inhibition factor (MIF) is a chemokine like functional chemokine, CXCL12 and MIF together play important roles in As through CXC chemokine receptor 4 (CXCR4). The CXCL12-CXCR4 bioaxis is an important chemokine/chemokine receptor axis that can regulate various biological behaviors such as cell proliferation, mobilization, differentiation, homing, and chemotaxis. Numerous studies have found that it widely affects various cells related to As and is closely related to the formation and development of As plaques. Therefore, the CXCL12/MIF-CXCR4 bioaxis is expected to become a more precise target for As treatment, and regulating the CXCL12/MIF-CXCR4 bioaxis strategy provides new ideas for the prevention and treatment of As.