Cellular responses to high glucose are numerous and varied but ultimately result in functional changes and, often, cell death. High glucose induces oxidative and nitrosative stress in many cell types causing the generation of species such as superoxide, nitric oxide and peroxynitrite and their derivatives. The role of these species in high glucose-mediated apoptotic cell death is relevant to the complications of diabetes such as neuropathy, nephropathy and cardiovascular disease. High glucose causes activation of several proteins involved in apoptotic cell death, including members of the caspase and Bcl-2 families. These events and the relationship between high glucose-induced oxidative stress and apoptosis are discussed here with reference to additional regulators of apoptosis such as the mitogen-activated protein kinases (MAPKs) and cell-cycle regulators.