Human calciphylaxis reflects a form of severe tissue compromise attributable to a unique microangiopathy that combines features of vascular thrombotic occlusion with endoluminal calcification. While most frequently described in patients with renal failure, it is seen in other settings, such as multiple myeloma; polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome; cirrhosis; and rheumatoid arthritis. Although most commonly involving the skin, calciphylaxis can affect other organs including the heart and gastrointestinal tract, in which cases it falls under the appellation of systemic calciphylaxis. There are cases in which the main pathology is one of endovascular thrombosis of the vessels of the fat without discernible calcification or one manifesting a pseudoangiosarcomatous pattern, hence adding to the histomorphologic spectrum of calciphylaxis. A variety of factors contribute to this severe occlusive microangiopathy, including an underlying procoagulant state and ectopic neo-osteogenesis of the microvasculature through varied mechanisms, including increased osteopontin production by vascular smooth muscle or reduced synthesis of fetuin and GLA matrix protein, important inhibitors of ectopic neo-osteogenesis. Certain factors adversely affect outcome, including truncal and genital involvement and systemic forms of calciphylaxis. With a better understanding of its pathophysiology, more-effective therapies, such as sodium thiosulfate and biphosphanates to reduce reactive oxygen species and receptor activator of nuclear factor κβ-mediated nuclear factor κβ activity, respectively, are being developed.