Transient receptor potential (TRP) channels of the melastatin-like family (TRPM) play critical roles in mediating cellular responses to a wide range of physiological stimuli that, under certain situations, can induce cell death. To date, two TRPM family members, TRPM2 and TRPM7, have been implicated directly as central components of cell death pathways. TRPM2, a Ca²⁺-permeant, non-selective cation channel, senses and responds to oxidative stress levels in the cell. TRPM7 is required for cell viability and has been proposed recently to mediate stress-induced cell death in the central nervous system. We review here the evidence for the involvement of these TRPM channels in cell death processes and discuss the mechanisms by which TRPM channel activation occurs. The ability to attenuate expression levels and functionality of these channels is necessary to understand the involvement of TRPM in cell death and we evaluate current approaches for modulation of TRPM channel function. Finally, we discuss the possibility that TRPM channels may provide therapeutic targets for degenerative diseases involving oxidative stress-related pathologies including diabetes and Alzheimer’s disease.