The 'mitochondrial permeability transition', characterized by a sudden induced change of the inner mitochondrial membrane permeability for water as well as for small substances (</=1.5 kDa), has been known for three decades. Research interest in the entity responsible for this phenomenon, the 'mitochondrial permeability transition pore' (mPTP), has dramatically increased after demonstration that it plays a key role in the life and death decision in cells. Therefore, a better understanding of this phenomenon and its regulation by environmental stresses, kinase signalling, and pharmacological intervention is vital. The characterization of the molecular identity of the mPTP will allow identification of possible pharmacological targets and assist in drug design for its precise regulation. However, despite extensive research efforts, at this point the pore-forming core component(s) of the mPTP remain unidentified. Pivotal new genetic evidence has shown that components once believed to be core elements of the mPTP (namely mitochondrial adenine nucleotide translocator and cyclophilin D) are instead only mPTP regulators (or in the case of voltage-dependent anion channels, probably entirely dispensable). This review provides an update on the current state of knowledge regarding the regulation of the mPTP.