It is somewhat puzzling that 22 of the 24 Tas2rs examined encode variant proteins in B6 and D2 mice even though these strains exhibit similar taste responses to bitter compounds such as DB or cyclohexamide [47]. Taken together, these observations suggest that Tas2rs are quite tolerant of variation, and that perhaps most of the differences observed do not affect domains important for ligand interactions or receptor-mediated signaling mechanisms. Interestingly, 23% of missense mutations in D2 Tas2rs affect the first two extracellular loops of the receptors. These two loops have been recently shown to affect the ligand response profiles of some T2Rs [23]. More systematic analyses of structure-function relationships between these T2R variants and an array of bitter stimuli are necessary to determine which changes may impact ligand binding, interactions with other proteins, or overall receptor structure.