CD40-CD40 ligand (CD40L) interactions play a central role in the development and progression of atherosclerosis. In the late 1990s, we and others have shown that complete inhibition of the CD40L signaling pathway resulted in a decrease in atherosclerosis and in the induction of a stable atherosclerotic plaque phenotype. These stable plaques contained high amounts of collagen and vascular smooth muscle cells, whereas the amount of macrophages and T lymphocytes was low. Because clinical complications of atherosclerosis are mostly the result of plaque rupture, induction of plaque stability would significantly reduce the morbidity and mortality of atherosclerosis and thus validates inhibition of the CD40L system as a therapeutic target for atherosclerosis. However, long-term inhibition of this system probably compromises the immune system of the patient. Therefore, it is desirable to target either the downstream signaling modulators of the CD40-CD40L system that are associated with atherosclerosis, or target the CD40-CD40L system in a local, cell type-specific way. This is likely to induce plaque stabilization with limited systemic side effects, and a significant reduction of cardiovascular disease.