The sweetness of sugar is regarded by humans as the optimal sensation; that of alternative non-sugar sweeteners possesses an inferior sweet quality, which limits their use in low-calorie foods. These sweeteners may produce bitter, metallic or cooling sensations, as well as lingering sweet aftertaste. The molecular basis for these undesirable sensations is poorly understood. Although various sweeteners may stimulate the same G-protein-coupled taste receptors (GPCRs), inferior sweet-taste quality is uniquely related to some non-sugar sweeteners. This chapter presents data indicating that such tastants may rapidly permeate taste cells under physiological conditions in vivo and interact with downstream signaling components such as signal-termination-related kinases in vitro. The implications of these properties for sweet-taste quality are discussed.