Oxygen, a necessary element for the life of a cell, is also the source of active states of oxygen including radicals, which can disrupt cell structure and alter cell function. Increasing evidence indicates that active oxygen species are formed in response to tumor promoters and that the cellular consequences of their actions may play a role in the process of tumor promotion. This report summarizes work from our laboratory that implicates active oxygen species derived in part from phagocytic cells in the tumor promotion process by phorbol esters and other promoters in mouse skin. Work from other laboratories indicates that phorbol ester promoters stimulate the production of active states of oxygen in mouse skin epidermal cells in vivo and in vitro. Oxidative DNA damage in epidermal cells from mice treated topically with the potent promoter phorbol myristate acetate has also been reported. The production of active states of oxygen including free radicals is discussed in relation to the mode of action of complete, first, and second stage promoters in the multistage carcinogenesis model in mouse skin.