This review focuses on the role of cyclophilin D (CypD) as a prominent mediator of the mitochondrial permeability transition pore (MPTP) and subsequent effects on cardiovascular physiology and pathology. Although a great number of reviews have been written on the MPTP and its effects on cell death, we focus on the biology surrounding CypD itself and the non-cell death physiologic functions of the MPTP. A greater understanding of the physiologic functions of the MPTP and its regulation by CypD will likely suggest novel therapeutic approaches for cardiovascular disease, both dependent and independent of programmed necrotic cell death mechanisms.  (Circ J 2013; 77: 1111–1122)