Mitochondria are now known to play a critical role in initiating both apoptotic and necrotic cell death. A major player in this process is the Mitochondrial Permeability Transition Pore (MPTP), a non-specific pore that opens in the inner mitochondrial membrane under conditions of elevated matrix [Ca2+], especially when this is accompanied by oxidative stress and depleted adenine nucleotides. These are exactly the conditions which occur during reperfusion of a tissue following a period of ischaemia and lead to "reperfusion injury". Data from this and other laboratories have led to the proposal that the MPTP is formed through a calcium-mediated conformational change of the adenine nucleotide translocase (ANT), facilitated by bound cyclophilin-D (CyP-D). CyP-D binds tightly to the ANT following modification of critical thiol groups by oxidative stress which also cause adenine nucleotides to dissociate from their binding sites on the ANT. Most recently we have confirmed this model by showing that the MPTP can be reconstituted into proteoliposomes using purified ANT and CyP-D. The extent of MPTP opening in the Langendorff perfused heart has been determined using mitochondrial entrapment of [3H]-2-deoxyglucose. The MPTP does not open in the ischaemic heart, but does do so during subsequent reperfusion, although later in reperfusion it can close again and the extent of closure correlates with functional recovery of the heart. The implications of this for necrotic versus apoptotic cell death in reperfusion injury will be discussed. A range of protocols that minimise opening of the MPTP are shown to protect both Langendorff and working hearts from reperfusion injury; these include addition of cyclosporin A, propofol and pyruvate to the perfusion medium prior to ischaemia. Collaborative studies with the laboratory of Tadeusz Weiloch suggest a similar role for the MPTP in the cell death occurring in the hippocampus following ischaemia/reperfusion or hypoglycaemia/normoglycaemia. Data will be presented that demonstrate that in some systems (e.g. the action of tumour necrosis factor a) cytochrome c release from mitochondria and induction of apoptosis may be independent of the MPTP.