Many low-molecular weight molecules, including amino acids, saccharides, polyols, peptides, and synthetic compounds, are well known to elicit the sensation of sweetness, whereas most proteins are tasteless and flavorless. However, some proteins do elicit a sweet taste response on the human palate. Sweet-tasting proteins have potential as low-calorie sweeteners and as substitutes for sucrose for industrial applications, and could be useful in clarifying the mechanisms by which we perceive a sweet taste. However, despite a number of investigations assessing the relationship between sweetness and the structures of sweet-tasting proteins, no common feature has been identified in either their tertiary structures or amino acid sequences. However, most sweet-tasting proteins are basic and have high isoelectric points. Here, we first review site-directed mutagenesis and chemical modification studies on the charged residues of thaumatin and lysozyme. Efforts to increase the production yield of recombinant lysozyme and thaumatin from the yeast Pichia pastoris are then described. We conclude by introducing our recent investigations into the atomic-resolution structural analysis of thaumatin, and a cell-based assay using sweet taste receptors.