Vascular calcification is closely associated with morbidity and mortality in patients with chronic kidney disease, atherosclerosis and diabetes. In the past few decades, vascular calcification has been studied extensively and the findings have shown that the mechanism of vascular calcification is not merely a consequence of a high-phosphorus and high-calcium environment but also an active process characterized by abnormal calcium phosphate deposition on blood vessel walls that involves various molecular mechanisms. Recent advances in bioinformatics approaches have led to increasing recognition that aberrant post-translational modifications (PTMs) play important roles in vascular calcification. This review presents the latest progress in clarifying the roles of PTMs, such as ubiquitination, acetylation, carbamylation and glycosylation, as well as signaling pathways, such as the Wnt/β-catenin pathway, in vascular calcification.