Widespread vascular calcification is a ubiquitous feature of aging and is prevalent in association with a number of common pathologies including atherosclerosis, renal failure, and diabetes. Once thought of as innocuous, emerging evidence suggests that calcification is causal in precipitating vascular events and mediating chronic cardiovascular damage, independent of disease context. Importantly, a large body of data has shed light on the factors that favor the formation of calcification in vivo, as well as on the complex mechanisms that initiate and promote it. This has identified some novel targets and allowed for the possibility that calcification can potentially be blocked and ultimately regressed. Targets include local and circulating inhibitors of calcification as well as factors that may ameliorate vascular smooth muscle cell (VSMC) apoptosis. Despite this, the vasculature remains a difficult tissue to target and currently there are no effective treatments in general use. More crucially, any potential treatments will need to be carefully evaluated as they may impinge on bone metabolism. Our best hope for the near future is to normalize factors associated with accelerated calcification in pathologies such as renal failure where, aberrant mineral metabolism, as well as treatment regimes, may contribute to the initiation and progression of calcification.