Vascular calcification is a major risk factor for cardiovascular morbidity and mortality. A full understanding of the signalling pathways mediating vascular calcification is crucial not just because of the importance of this pathology in disease, but also for exploring potential therapeutic targets. Clinically there is a need to develop therapies to prevent or even reverse calcification in situations of atherosclerosis, chronic kidney disease, diabetes, and aging. In this brief review, we intend to explore the initial triggers, which are commonly related to calcification in different disease scenarios and examine the downstream signalling pathways that instigate the process of vascular calcification. In particular, we try to dissect these pathways and also examine cross-talk between different signalling pathways. Our focus is the vascular smooth muscle cell (VSMC) as it is ultimately the phenotypic modulation of these cells that may drive the calcification process.