1. Physiological and behavioral responses to artificial sweeteners, natural sweeteners, and cyclic nucleotides were assessed using two techniques. An extracellular "in situ" technique recorded action potentials from fungiform taste buds and the two-bottle preference test measured behavioral preferences for the different sweeteners. 2. Two high-potency sweeteners, NC-00274-01 (NC01) and NC-00044-AA (NCAA), were preferred over water at micromolar concentrations. Saccharin and sucrose were likewise preferred, but at millimolar concentrations. 3. Bursts of action currents were elicited by sucrose at 200 mM, saccharin at 20 mM, and NCAA at 0.1 mM. A concentration-response curve for the high-potency sweetener NC01 revealed a threshold concentration of 1 microM and a saturation concentration of 100 microM. No responses were elicited by aspartame. 4. The responses to different sweeteners adapted rapidly at saturating concentrations. With NC01, adaptation was concentration dependent: at threshold the response adapted very slowly if at all. Adaptation increased with increasing concentration. 5. Membrane-permeant analogues of adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate mimicked sweeteners in their ability to elicit a response. This occurred with high fidelity: nearly every taste bud that responded to sweeteners also responded to the nucleotides and every sweet-unresponsive taste bud was nucleotide unresponsive. 6. The sweet responses and nucleotide responses occurred in the absence of permeant apical cations and were not enhanced nor diminished by the presence of such cations. Amiloride had no effect on the sweet response.