Medial artery calcification (MAC) is a characteristic feature of diabetes. MAC represents a concentric calcification that proceeds via matrix vesicle-nucleated mineralization accompanied with apatitic calcium phosphate deposits in the arterial tunica media in the absence of atheroma and neointima. Multiple factors contribute to the induction and progression of diabetic MAC including inflammation, oxidative stress, adiposity, insulin resistance, advanced glycation end-products, and hyperphosphatemia. Osteoblast-like cells form in the vessel wall from vascular smooth muscle cells and multipotent vascular mesenchymal progenitors. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, Osterix, and RUNX2 are crucial in the programming of osteogenesis. Currently, no therapy is available to reverse vascular calcification. Available therapies can only reduce and slow the progression of vascular calcification. Targeting regulatory proteins and enzymes directly involved in osteochondrogenesis and hydroxyapatite accumulation in the vascular wall may be beneficial for generating new efficient anti-calcific drugs.