Atherosclerotic plaque calcification represents a common pathophysiologic process in the advanced phases of the disease. Both inflammatory and vascular cells (such as osteoblast-like cells, osteoclast-like cells, dendritic cells, macrophages, smooth muscle cells, and endothelial cells) are active players in the balance between intraplaque bone deposition and resorption. Inflammatory processes underlying plaque calcification are regulated by soluble mediators that also contribute to plaque destabilization and increased vulnerability. Among different mediators, the receptor activator of nuclear factor-kappa B (NF-kappa B) ligand (RANKL)/osteoprogerin (OPG) system is a major determinant in inflammatory cell differentiation toward osteoclast-like cells. Thus, this system might be a promising parameter to be investigated as a marker of calcification-related cardiovascular risk and a therapeutic target. Despite some promising results, several limitations have been shown in the potential clinical use of serum RANKL/OPG to better assess the cardiovascular risk. At present, the potential relationship between RANKL/OPG and the content of calcium within the intima of the coronary arteries (CAC score, assessed by computed tomography) needs to be explored in large clinical studies. On the other hand, the antiatherosclerotic relevance of treatments antagonizing RANKL is still under investigation. Despite that clinical evidence is needed, this therapeutic approach might be of particular benefit in selective populations (such as rheumatoid arthritis patients) with an increased cardiovascular risk.