In this article, I present an evolutionary explanation for why organisms respond to inhaled anesthetics. It is conjectured that organisms today respond to inhaled anesthetics owing to the sensitivity of ion channels to inhaled anesthetics, which in turn has arisen by common descent from ancestral, anesthetic-sensitive ion channels in one-celled organisms (i.e., that the response to anesthetics did not arise as an adaptation of the nervous system, but rather of ion channels that preceded the origin of multicellularity). This sensitivity may have been refined by continuing selection at synapses in multicellular organisms. In particular, it is hypothesized that 1) the beneficial trait that was selected for in one-celled organisms was the coordinated response of ion channels to compounds that were present in the environment, which influenced the conformational equilibrium of ion channels; 2) this coordinated response prevented the deleterious consequences of entry of positive charges into the cell, thereby increasing the fitness of the organism; and 3) these compounds (which may have included organic anions, cations, and zwitterions as well as uncharged compounds) mimicked inhaled anesthetics in that they were interfacially active, and modulated ion channel function by altering bilayer properties coupled to channel function. The proposed hypothesis is consistent with known properties of inhaled anesthetics. In addition, it leads to testable experimental predictions of nonvolatile compounds having anesthetic-like modulatory effects on ion channels and in animals, including endogenous compounds that may modulate ion channel function in health and disease. The latter included metabolites that are increased in some types of end-stage organ failure, and genetic metabolic diseases. Several of these predictions have been tested and proved to be correct.