Macrophages, smooth muscle cells (SMCs), and their interactions have key roles in the pathogenesis of atherosclerotic vascular diseases. In atheroma development, the phenotype of macrophages and SMCs change, which may influence the disease progression. Accumulating data on the phenotypes exhibited by these cells within atherosclerotic lesions raise many questions regarding the mechanisms and factors that might control the transition of cell phenotype. SMCs often reside in vascular lesions in close proximity to macrophage clusters and are most likely influenced by factors released from these proinflammatory phagocytes. Moreover, macrophages may be influenced by direct contact with SMCs or soluble factors released by these cells. Macrophages may promote activation and induce proatherogenic functions of SMCs, and SMCs may modulate macrophage phenotype. Addressing the mechanisms involved in SMC-macrophage crosstalk that lead to phenotypic modulation of both cell types may provide new insight into atherogenesis and new targets for therapies of various vascular diseases.