The S-nitrosoglutathione (GSNO)-metabolizing enzyme, GSNO reductase (GSNOR), is a central regulator of protein S-nitrosylation. Accumulating data suggests that GSNOR inhibition might be a useful therapeutic strategy, but the in vitro and in vivo effects of GSNOR inhibitors have not been fully investigated. We have found that a GSNOR inhibitor (GSNORi) can increase protein S-nitrosylation, and induce nitrosative response pathways, in macrophage stimulated to express the inducible isoform of NO synthase (NOS2). More recently, we have found that NOS2 is important for modulation of allergic asthma phenotypes by GSNORi. We will discuss these findings and their implications for GSNORi therapy in acute and chronic inflammatory diseases.