Vascular calcification (VC) is one of the most dramatic consequences of chronic kidney disease (CKD). It has been considered a passive process, resulting essentially from mineral metabolism disorders and alterations in calcium and phosphate balance. But during the last decade, it has been elucidated how VC is not only a passive but more properly an active process, in which different factors are deeply involved. The progression of vessel wall mineralization is commonly associated with factors that promote VC, such as age, dialysis vintage and mineral metabolism abnormalities. Furthermore, many substances seem to be dynamically implicated in the regulation of the molecular mechanisms of VC. Between them, the matrix Gla protein and fetuin-A have recently been investigated in CKD. In this review, along with the most promising possible treatments, the new molecular mechanisms involved in the VC process will be elucidated.