Nutrient-sensing mechanisms have emerged as the fringe articulating nutritional needs with dietary choices. Carbohydrate, amino acid, fatty acid, mineral, and water-sensing receptors are highly conserved across mammals and birds, consisting of a repertoire of 22 genes known to date. In contrast, bitter receptors are highly divergent and have a high incidence of polymorphisms within and between mammals and birds and are involved in the adaptation of species to specific environments. In addition, the expression of nutrient-sensing genes outside the oral cavity seems to mediate the required decision-making dialogue between the gut and the brain by translating exogenous chemical stimuli into neuronal inputs, and vice versa, to translate the endogenous signals relevant to the nutritional status into specific appetites and the control of feed intake. The relevance of these sensors in nondigestive systems has uncovered fascinating potential as pharmacological targets relevant to respiratory and cardiovascular diseases.