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Nitric oxide (•NO) is a biologically important short-lived free radical signaling molecule. Both the enzymatic synthesis and the predominant forms of cellular metabolism of •NO are oxygen-dependent. For these reasons, changes in local oxygen concentrations can have a profound influence on steady-state •NO concentrations. Many proteins are regulated by •NO in a concentration-dependent manner, but their responses are elicited at different thresholds. Using soluble guanylyl cyclase (sGC) and p53 as model •NO-sensitive proteins, we demonstrate that their concentration-dependent responses to •NO are a function of the O2 concentration. p53 requires relatively high steady-state •NO concentrations (>600 nM) to induce its phosphorylation (P-ser-15), whereas sGC responds to low •NO concentrations (, Graphical Abstract Highlights ►► O2 regulates •NO signaling by modulating •NO synthesis and metabolism. ► O2 affects •NO synthesis by regulating NOS expression and substrate availability. ► The rate of enzymatic •NO production increases linearly from 1–8% O2. ► The rate of cellular •NO metabolism increases with increasing [O2]. ► •NO-mediated sGC activation is maximal between 5% and 8% O2.