Vascular calcification is a ubiquitous feature in the ageing population and is associated with increased mortality, morbidity and surgical intervention. It occurs at two anatomical sites in the vessel wall; the intima in association with atherosclerosis while medial calcification is prevalent in diabetes and renal failure. These calcifications were once considered to be due to passive degenerative processes however, accumulating evidence suggests that calcification is driven by cell-mediated processes similar to bone formation. Vascular smooth muscle cells (VSMCs) uniquely orchestrate the calcification process. Unlike other contractile muscle cell types VSMCs are not terminally differentiated. In response to injury they can undergo phenotypic modulation to become proliferative and migratory and deposit a modified extracellular matrix (ECM); with this phenotypic transition essential to repair the vessel wall and stabilize atherosclerotic plaques. The factors that regulate VSMC phenotypic transition are still poorly understood however it is clear that prolonged exposure to stress and ageing perturb these repair processes. The ultimate outcome of this failed repair is calcification and a number of VSMC-mediated processes are required for calcification to occur. An immediate and consistent feature of the VSMC phenotypic transition is the induction of osteo/chondrocytic differentiation. This phenotype is characterized by upregulation of a number of mineralization-regulating proteins and ECM components normally expressed in bone. The most important of these is the master bone regulatory transcription factor (TF) Runx2 which activates its putative targets alkaline phosphatase (ALP), bone sialoprotein (BSP) and osteocalcin (OCN). The role of these osteo/chondrocytic proteins in VSMC function is not clear but their expression in vivo co-localizes with sites of calcification. Other key events in the induction of calcification are loss of expression/function of local (Matrix Gla protein (MGP)) and circulating (fetuin-A) inhibitors of calcification. In addition, apoptosis as well as membrane bound vesicles released from phenotypically modified VSMCs have an essential role in promoting calcification by forming the first nidus for mineralization. Taken together, our studies suggest that vascular calcification is a clinically quantifiable ‘read-out’ of vascular damage, induced by a multitude of factors including mineral overload and oxidative, mechanical or genotoxic stress. Studies focussing on the specific factors that induce a ‘calcific milieu’ in patients as well as factors that may be targeted for intervention such as (1) increasing inhibitor function and (2) blocking maladaptive signalling that promotes osteogenic differentiation, are now key to ameliorating these disease processes.