Mitochondria are implicated in many important cellular functions covering the whole life cycle from mitochondrial biogenesis to cell death. Mitochondrial homeostasis is tightly regulated, and mitochondrial dysfunction is frequently associated with severe human pathologies (eg, cardiovascular diseases, cancer, and neurodegeneration). The permeability transition pore (PTP) is an unselective voltage-dependent mitochondrial channel. Despite the extensive use of electrophysiology, biochemistry, pharmacology, and genetic invalidation in mice, the molecular identity of PTP is still unknown. Nevertheless, PTP is central to mitochondrial vital functions and can play a lethal role in many pathophysiological conditions. This review recapitulates the current knowledge of the various modes of conductance of the PTP channel and discusses their implication in the physiological roles of PTP and their regulation. Based on its involvement in normal physiology and human pathology, a better understanding of this channel and its roles remains a major goal for basic scientists and clinicians.