Prolonged odor exposure causes a specific, reversible adaptation of olfactory responses. A genetic screen for negative regulators of olfaction uncovered mutations in the cGMP-dependent protein kinase EGL-4 that disrupt olfactory adaptation in C. elegans. G protein-coupled olfactory receptors within the AWC olfactory neuron signal through cGMP and a cGMP-gated channel. The cGMP-dependent kinase functions in AWC neurons during odor exposure to direct adaptation to AWC-sensed odors, suggesting that adaptation is a cell intrinsic process initiated by cGMP. A predicted phosphorylation site on the beta subunit of the cGMP-gated channel is required for adaptation after short odor exposure, suggesting that phosphorylation of signaling molecules generates adaptation at early time points. A predicted nuclear localization signal within EGL-4 is required for adaptation after longer odor exposure, suggesting that nuclear translocation of EGL-4 triggers late forms of adaptation.