TRPM channels are a subgroup of the transient receptor potential (TRP) channel superfamily whose members have important roles in cell proliferation and survival. TRPM2, the second subfamily member to be cloned, is expressed in many tissues including brain, heart, vasculature and haematopoietic cells. TRPM2 is activated by oxidative stress and several other extracellular signals including tumour necrosis factor α (TNF‐α) and amyloid β‐peptide, which increase production of ADP‐ribose (ADPR). ADPR binds to the TRPM2 C‐terminal NUDT9‐H domain, activating the channel. Early studies support the paradigm that TRPM2 activation induces cell death by sustained Ca2+ influx or by enhancing cytokine production, aggravating inflammation and tissue injury. However, more recent data show that for a number of physiological processes, TRPM2 is protective. TRPM2 protects lungs from endotoxin‐induced injury by reducing reactive oxygen species (ROS) production by phagocytes. It protects hearts from oxidative damage after ischaemia–reperfusion or hypoxia–reoxygenation by maintaining better mitochondrial bioenergetics and by decreasing ROS. Sustained Ca2+ entry through TRPM2 is required to maintain cellular bioenergetics and protect against hypoxia–reoxygenation injury. TRPM2 also protects neuroblastoma from moderate oxidative stress by decreasing ROS through increased levels of forkhead box transcription factor 3a (FOXO3a) and a downstream effector, superoxide dismutase 2. TRPM2 is important for tumour growth and cell survival through modulation of hypoxia‐inducible transcription factor expression, mitochondrial function and mitophagy. These findings in cardiac ischaemia and in neuroblastoma suggest that TRPM2 has a basic role in sustaining mitochondrial function and in cell survival that applies to a number of physiological systems and pathophysiological processes including ischaemia–reperfusion injury. Although activation of the ion channel TRPM2 can induce cell death in some circumstances, TRPM2 can also preserve cell viability and protect against tissue damage following oxidative stress and ischaemia–reperfusion. TRPM2 dependent Ca2+ entry can modulate HIF‐1/2α expression. One mechanism through which this may occur is through enhancement of calcineurin activity through TRPM2‐dependent Ca2+ entry, which may increase HIF‐1/2α stability. HIF‐1/2α enhances expression of a number of target genes including those involved in energy metabolism, antioxidant expression and mitophagy. Ca2+ entry through TRPM2 may also directly influence mitochondrial Ca2+ uptake. Together, the impact on mitochondrial function results in reduced ROS production and reduced cell death. In contrast, in the TRPM2 KO, Ca2+ influx is reduced after oxidative stress and HIF‐1/2α expression is decreased, as are proteins downstream of HIF‐1/2α including BNIP3, SOD1/2, and NDUFA4L2. In addition, mitochondrial Ca2+ uptake is reduced, which may contribute to dysfunctional mitochondria along with decreased NDUFA4L2, and reduced mitochondrial bioenergetics. Decreased BNIP3, which results in reduced mitophagy, contributes to an accumulation of dysfunctional mitochondria and along with decreased SOD1/2 antioxidant activity, increased ROS. The cell has reduced tolerance to a further rise in ROS, for example following ischaemia or doxorubicin, leading to reduced cell survival and increased cell death in the absence of TRPM2.