In the work of Wiener et al. 1,360 hypothetically non-bitter flavor compounds are assumed as the non-bitterants for the bitter/bitterless classification (Dagan-Wiener et al., 2017). However, some of hypothetically non-bitter flavors are small and volatile odorous molecules, which are modulated by about 400 olfactory receptors to give rise to the sense of smell (Hauser et al., 2017). As we know, the olfactory receptors, belonging to the class A family of GPCRs, possess the binding pocket in the TMD domain (Sayako et al., 2008), meanwhile, 25 hTas1Rs, arguably categorized as class A family of GPCRs, have the binding site in the TMD domain as well (Di Pizio et al., 2016). Hence some of these small odorants may still have chances to promiscuously activate hTas2Rs to elicit the bitterness. Hence, caution should be taken in the use of hypothetically non-bitter flavors.