Toxic epidermal necrolysis (TEN) is a dramatic drug-induced reaction that may lead to full destruction of the epidermis and epithelial mucosae. The keratinocytes themselves seem to play a major role in the pathogenic mechanism. Biochemical and morphological studies performed on early epidermal lesions demonstrated that keratinocytes undergo apoptosis, but histological and clinical data show evidence of necrosis of the epidermis later in the disease evolution. Based on the limited information currently available about TEN pathomechanism, we present a 'mitochondrial hypothesis' that may explain both early apoptosis and late necrosis in TEN epidermis. Strong electrophilic drug metabolites are generated in TEN-affected keratinocytes due to an impaired detoxication pathway. These compounds presumably disrupt the electron transfer chain in the mitochondriae resulting in a decline in ATP production, loss of electrochemical gradient across the inner membrane (Deltapsim), and partial reduction in O2 with production of reactive oxygen species (ROS). The latter compounds directly damage cell membranes and act as intracellular chemical messengers stimulating proapoptotic systems such as CD95 and TNF-alpha, which in turn can activate nitric oxide (NO) metabolism. NO interacts with ROS to enhance their toxic effects. These proapoptotic events represent swift processes in the involved cells. The loss of Deltapsim and the opening of permeability transition pores in the mitochondrial membrane lead to osmotic swelling and rupture of these organelles with subsequent necrosis of the cell. The necrotic events follow apoptosis when both phenomena are present.