While the majority of sweet substances are of low- molecular-weight, there are six proteins, brazzein, thaumatin, mabinlin, monellin, neoculin and pentadin, that elicit sweetness to humans. These substances as non-glycemic sweeteners will provide a potential use for people with obesity, diabetes and other metabolic syndromes. Neoculin (NCL) occurring in the tropical fruits of Curculigo latifolia is currently the only protein that has both sweetness and taste-modifying activity to convert sourness into sweetness. The strong sweetness of NCL makes it possible to use this substance as a tool for basic taste signaling research as well. However, it has remained unclear how NCL induces this unique sensation. Recently, we quantitatively evaluated the acid-induced sweetness of NCL by a cell-based assay. In brief, human sweet taste receptor hT1R2-hT1R3 was functionally expressed, together with chimeric Gα, in cultured cells. The cells responded to NCL pH-dependently under acidic conditions. The pH-response relationship reflected a sigmoidal, imidazole titration curve suggesting the involvement of histidine residues in the acid-induced sweetness. Actually, an NCL variant, in which all the five histidine residues were replaced with alanine, elicited strong sweetness at neutral as well as acidic pH. The His→Ala variant is apparently a novel sweet protein genetically engineered. This review focuses on a molecular logic of the taste-modification event in view of the potential application of NCL and its variant.