Macrophages and smooth muscle cells (SMCs) represent major players in the pathogenesis of atherosclerotic vascular diseases. SMCs often reside in close proximity to macrophage clusters. Activated macrophages may promote pro-atherogenic functions of SMCs. Addressing macrophage-dependent mechanisms of SMC activation may provide new insight into atherogenesis and new therapies for various vascular diseases. Direct evidence for such interplay between atherosclerosis-associated cell types, however, remains scant. While SMC-derived macrophage foam cells have long been reported, recent evidence has also identified SMC-like cells of monocyte origin, suggesting dynamic interchangeability of these cell types. Future efforts may help to understand the interplay between key cell types and offer new paradigms in vascular medicine and pharmacology.