S -nitrosothiol signaling reactions are argued to play key modulatory roles in mediating the actions of NOS in health and disease. A report by Palmer et al. in this issue of the JCI provides new insight into the in vivo biology of S-nitrosothiols (see the related article beginning on page 2592). The authors examine the chronic effects of exogenous nitrosothiol therapy and demonstrate that the commonly used antioxidant N-acetylcysteine (NAC) induces pulmonary arterial hypertension in mice. Importantly, the authors argue that the vascular pathology they observe in the lungs of these animals is functionally and morphologically equivalent to that observed in chronic hypoxia. These findings raise the concern that chronic NAC therapy may induce similar vascular pathology in patients.