The effector role of mitochondria in cell death regulation is accomplished by massive Ca2+ release, by unbalanced ROS generation and by inhibition of ATP production which eventually affects all cellular energy-dependent processes. The mitochondrial permeability transition pore (PTP) is an inner mitochondrial membrane megachannel which acts as a key switch to mitochondrial dysfunction, and integrates Ca2+- and ROS-dependent stimuli. Stable opening of the PTP constitutes a point of no-return in cell commitment to death, as it results in mitochondrial membrane depolarization, mitochondrial swelling, and rupture of the outer mitochondrial membrane. Open-closed transitions of the pore are strictly regulated. An altered PTP-dependent mitochondrial dysfunction can lead to changes in the response to apoptogenic stimuli, and dysregulation of pore opening is therefore involved in several diseases. For instance, PTP inhibition might be a strategy used by tumor cells to escape death. Even if the molecular composition of the PTP remains unknown, it is established that pore opening is favored by the matrix peptidyl prolyl cis-trans isomerase cyclophilin (CyP-D). CyP-D can form a complex with the chaperone TRAP-1, and the latter displays a survival activity and is overexpressed in cells exposed to pro-apoptotic insults. Here I discuss the possibility that several signalling pathways converge on PTP regulation by targeting CyP-D and/or TRAP-1. These modes of pore tuning might be relevant in models of neoplastic transformation.