TRPM8, a member of the melastatin subfamily of TRP cation channels, is activated by voltage, low temperatures and cooling compounds. These properties and its restricted expression to small sensory neurons have made it the ion channel with the most advocated role in cold transduction. Recent work suggests that TRPM8 activation by cold and menthol takes place through shifts in its voltage activation curve, which cause the channel to open at physiological membrane potentials. In contrast, little is known about the actions of inhibitors on the function of TRPM8. We investigated the chemical and thermal modulation of TRPM8 in transfected HEK293 cells and in cold-sensitive primary sensory neurons. We show that cold-evoked TRPM8 responses are effectively suppressed by inhibitor compounds SKF96365, BCTC and 1,10-phenanthroline. These antagonists exert their effect by shifting the voltage dependence of TRPM8 activation towards more positive potentials. An opposite shift towards more negative potentials is achieved by the agonist menthol. Functionally, the bidirectional shift in channel gating translates into a change in the apparent temperature threshold of TRPM8-expressing cells. Accordingly, in presence of the antagonist compounds, the apparent response threshold temperature of TRPM8 is displaced towards colder temperatures, while menthol sensitizes the response, shifting the threshold in the opposite direction. Co-application of agonists and antagonists produces predictable cancellations of these effects, suggesting the convergence upon a common molecular process. The V1/2 of TRPM8 activation by cold was ~140 mV more negative in native channels compared to recombinant channels, with a much higher open probability at negative membrane potentials in the former case. In functional terms this difference translates into a shift in the apparent temperature threshold for activation towards higher temperatures for native currents. This difference in voltage-dependence readily explains the high threshold temperatures characteristic of many cold thermoreceptors. The modulation of TRPM8 activity by different chemical agents unveils an important flexibility in the temperature-response curve of TRPM8 channels and cold thermoreceptors.