Motor neuron survival is highly dependent on trophic factor supply. Deprivation of trophic factors results in induction of neuronal NOS, which is also found in pathological conditions. Growing evidence suggests that motor neuron degeneration involves peroxynitrite formation. Trophic factors modulate peroxynitrite toxicity (Estévez et al., 1995; Shin et al., 1996; Spear et al., 1997). Whether a trophic factor prevents or potentiates peroxynitrite toxicity depends upon when the cells are exposed to the trophic factor (Table 1). These results strongly suggest that a trophic factor that can protect neurons under optimal conditions, but under stressful conditions can increase cell death. In this context, it is possible that trophic factors or cytokines produced as a response to damage may potentiate rather than prevent motor neuron death. A similar argument may apply to the therapeutic administration of trophic factors to treat neurodegenerative diseases. Similarly, the contrasting actions of NO on motor neurons may have important consequences for the potential use of nitric oxide synthase inhibitors in the treatment of ALS and other related neurodegenerative diseases.