Reactive oxygen species are involved in cellular processes as diverse as proliferation and cell death. At concentrations that do not overwhelm the cellular antioxidant defense systems, reactive oxygen species such as superoxide anion can inhibit death signaling. The sensitivity of cells to apoptotic triggers is significantly increased upon decreasing intracellular superoxide concentration. The critical determinant is the tight intracellular balance between superoxide and hydrogen peroxide levels, and a shift from the tightly regulated physiological ratio could impact cellular response to death stimuli. A shift toward hydrogen peroxide leads to activation of the effector components of the cells' apoptotic machinery by inducing reduction of the intracellular milieu and a drop in cytosolic pH, thereby creating a facilitative environment for efficient death execution. Hence, we propose that a permissive apoptotic milieu is a function of decreased intracellular superoxide concentration and cytosolic acidification. (C) 2002 Elsevier Science (USA).