The detection of temperature and moisture is critical for survival. Flies must avoid thermal extremes and maintain appropriate body temperatures and hydration levels. The mechanisms by which thermo- and hygro-sensory stimuli are detected remain poorly understood. We find that members of the Ionotropic Receptor (IR) family of invertebrate sensory receptors have crucial roles in both of these sensory modalities. IRs are a large family of receptors (66 IRs in Drosophila melanogaster) that have been extensively studied as chemoreceptors. In the olfactory system, broadly expressed IR co-receptors like IR25a combine with more selectively expressed odor-specific IRs to create receptors conferring sensitivity to distinct chemicals. We now show that IR25a combines with members of a distinct group of “orphan” IRs (IRs not previously associated with chemical ligands) to confer sensitivity to thermo- and hygro-sensory stimuli and to drive thermo- and hygro-sensory behaviors. Analogous to IR25a-mediated chemosensing, we find that different IR combinations act in different neurons to mediate physiological and behavioral responses to distinct thermo- and hygro-sensory stimuli. Our data define a new set of combinatorial mediators of thermo- and hygro-sensation in Drosophila, and provide a new view of the relationship between these sensory modalities at a mechanistic level.