Despite the lack of its molecular identification, the mitochondrial permeability transition pore (PTP) is a fascinating subject because of its important role in cell death. This holds especially true for cardiovascular diseases and in particular for ischemia-reperfusion injury, where research on PTP inhibition has been successfully translated from bench to clinical evidence of cardioprotection. In fact, PTP opening is causally linked to the loss of cell viability as demonstrated by the reduction in infarct size obtained when PTP opening is counteracted by pharmacological inhibitors or by genetic ablation of cyclophilin D (CyPD). PTP opening favours ATP depletion, dysegulation of cellular Ca²⁺ homeostasis and oxidative stress, all of which synergize in jeopardizing cell survival. The sequence of events can be summarized as follows. PTP opening determines an immediate collapse of mitochondrial membrane potential that is followed by ATP depletion. When opening is prolonged, the initial uncoupling-like effect is rapidly followed by respiratory inhibition caused by loss of pyridine nucleotides and of cytochrome c. The resulting inhibition of electron flow might explain the increased ROS formation induced by PTP opening. Since the latter event is favoured by reactive oxygen species, a vicious cycle of injury amplification is likely to be established, especially at the onset of reperfusion. Here, besides summarizing the major factors controlling PTP opening the following controversial issues, will be addressed: (i) relationship with mitochondrial dynamics; (ii) potentially adverse effects elicited by prolonged CyPD inhibition; (iii) CyPD-independent inhibition of PTP opening.