Most heritable behavioral traits have a complex genetic basis, but few multigenic traits are understood at a molecular level. Here we show that the C. elegans strains N2 and CB4856 have opposite behavioral responses to simultaneous changes in environmental O₂ and CO₂. We identify two quantitative trait loci (QTL) that affect this trait and map each QTL to a single-gene polymorphism. One gene, npr-1, encodes a previously described neuropeptide receptor whose high activity in N2 promotes CO₂ avoidance. The second gene, glb-5, encodes a neuronal globin domain protein whose high activity in CB4856 modifies behavioral responses to O₂ and combined O₂/CO₂ stimuli. glb-5 acts in O₂-sensing neurons to increase O₂-evoked calcium signals, implicating globins in sensory signaling. An analysis of wild C. elegans strains indicates that the N2 alleles of npr-1 and glb-5 arose recently in the same strain background, possibly as an adaptation to laboratory conditions.