The mitochondrial permeability transition pore (PTP) is a high conductance channel of the inner membrane whose opening leads to an increase of permeability to solutes with molecular masses up to about 1500 Da, the 'permeability transition'. This potentially catastrophic event has long been known, yet the molecular bases for its occurrence remain unsolved despite its established importance in several in vivo models of pathology. Recent studies based on inactivation of genes encoding putative pore components (such as the adenine nucleotide translocators and the voltage-dependent anion channel) have raised major questions about the involvement of these proteins in PTP formation, yet they have conclusively demonstrated the role of matrix cyclophilin D as the mitochondrial receptor for the desensitizing effects of cyclosporin A. While the nature of the components forming the PTP remains controversial, the identification of novel inhibitors that can be used as affinity labels is offering new perspectives towards the molecular definition of the PTP.