Homeostasis of internal carbon dioxide (CO2) and oxygen (O2) levels is fundamental to all animals. Here we examine the CO 2 response of the nematode Caenorhabditis elegans. This species inhabits rotting material, which typically has a broad CO 2 concentration range. We show that well fed C. elegans avoid CO 2 levels above 0.5%. Animals can respond to both absolute CO 2 concentrations and changes in CO 2 levels within seconds. Responses to CO 2 do not reflect avoidance of acid pH but appear to define a new sensory response. Sensation of CO 2 is promoted by the cGMPgated ion channel subunits TAX-2 and TAX-4, but other pathways are also important. Robust CO 2 avoidance in well fed animals requires inhibition of the DAF-16 forkhead transcription factor by the insulin-like receptor DAF-2. Starvation, which activates DAF-16, strongly suppresses CO 2 avoidance. Exposure to hypoxia (<1% O2) also suppresses CO 2 avoidance via activation of the hypoxiainducible transcription factor HIF-1. The npr-1 215V allele of the naturally polymorphic neuropeptide receptor npr-1, besides inhibiting avoidance of high ambient O 2 in feeding C. elegans, also promotes avoidance of high CO 2. C. elegans integrates competing O 2 and CO2 sensory inputs so that one response dominates. Food and allelic variation at NPR-1 regulate which response prevails. Our results suggest that multiple sensory inputs are coordinated by C. elegans to generate different coherent foraging strategies.carbon dioxide sensing ͉ natural variation ͉ oxygen sensing C O 2 is an important sensory cue for many organisms. Insects can use elevated CO 2 as part of an alarm signal or to find food (1-3). In fungi, high CO 2 can induce filamentation (4) and regulate sporulation (5). Nematode parasites of plants and animals can follow CO 2 gradients to locate their hosts (6, 7). Internal CO 2 levels also provide important signals. For example, insects and mammals monitor internal CO 2 to modulate respiratory exchange (8-10). This homeostatic function prevents respiratory poisoning and pH changes in body fluids, which can occur if CO 2 levels rise above 5% (11).Several mechanisms have been implicated in sensing CO 2 . In Drosophila, avoidance of high CO 2 is mediated by a pair of odorant receptors (2, 12, 13). Artificially activating neurons expressing these receptors elicits the escape response (14). Less is known about how insects monitor internal CO 2 to control opening of spiracles (15). In mammals internal CO 2 levels regulate breathing, diuresis, blood pH, and blood flow (8). In most cases the molecular sensors involved are unclear although pH changes associated with hydration of CO 2 are thought to be important. Carbonic anhydrases, which catalyze the hydration of CO 2 to produce H ϩ and HCO 3 Ϫ , are widely expressed in mammals. HCO 3 Ϫ has been shown to regulate the activity of a family of adenylate cyclases that is conserved from bacteria to man (16). However, the role of these enzymes in CO 2 signaling in animals is unclear. In fungi an HCO 3 Ϫ -regulated adenylate cy...