Regulation of the intracellular calcium concentration is of critical importance in the determination of cell fate. Oxidative stress, through the production of oxygen metabolites including hydrogen peroxide, causes an increase in intracellular calcium, which results in cell injury, apoptosis, or necrosis. TRPM2, a member of the transient receptor potential (TRP) protein superfamily, is a widely expressed calcium-permeable cation channel that can be activated by micromolar levels of hydrogen peroxide and other reagents that produce reactive oxygen species. This channel is thought to be part of a physiological pathway through which hydrogen peroxide and TNFα may induce cell death.I demonstrate here, using RT-PCR, that TRPM2 mRNA is present in a human microglial cell line, C13. To elucidate the role of TRPM2 in oxidative stress-induced cell death in this line, cell death assays and Western analysis were used in combination with RNA silencing. In all assays there was no apparent differences between cells transfected with a random nonsense siRNA compared to non-transfected cells. TRPM2 specific siRNA successfully rescued C13 cells from concentrations of hydrogen peroxide that were otherwise fatal to these cells. Toxicity was determined by the methyl thiazole tetrazolium (MTT) assay as well as by flow cytometric analysis (FACS) of membrane phosphatidylserine redistribution. In a proportion of the cells phosphatidylserine flip was observed without an impairment of membrane integrity (propidium iodide remained excluded from the cells). This would be indicative of apoptosis. The cell death rescue was dependant on both the concentration of hydrogen peroxide and the time the cells were left to recover after a 45 minute treatment. Both endogenously produced and exogenously added hydrogen peroxide can activate the mitogen-activated protein (MAP) kinase superfamily. In this study, hydrogen peroxide added to intact C13 cells caused an increase in the activity of one such subfamily, the extracellular signal-regulated kinases (ERKs) as determined by an elevation of the phosphorylated forms. The increase was rapid but transient and more importantly, 30 minutes following hydrogen peroxide application, ERK activity had markedly declined below basal levels. In addition hydrogen peroxide also caused a decrease in Akt activity with an associated increase in glycogen synthase kinase 3αβ (GSK3αβ) activity. All of these signalling events have been shown to induce apoptosis and are therefore likely to contribute to the hydrogen peroxide-induced cell death in the C13 cell line. Knock-out of TRPM2 using siRNA technology completely prevented the depression below basal of the ERK activity and induced a partial rescue of the attenuated Akt activity. This would suggest that the hydrogen peroxide-mediated apoptosis, via the TRPM2 signalling cascade, involves both the ERK and PI3K-Akt pathways.