The cold receptor TRPM8, also designated CMR1, is a member of the transient receptor potential, TRP, family of excitatory ion channels. TRPM8 is a channel activated by cold temperatures, voltage and cooling compounds (McKemy, et al. 2002). In this study we characterize the cold- and voltage- induced activation of TRPM8 channel in an attempt to identify the temperature- and voltage-dependent components involved in channel activation. Under equilibrium conditions, decreasing temperature has two effects: a) it shifts the normalized conductance vs. voltage curves towards the left, along the voltage axis. This indicates that the degree of order is higher when the channel is in the open configuration. b) It increases the maximum channel open probability, suggesting that temperature affects both voltage-dependent and voltage-independent pathways. In the temperature range between 18 to 25 °C, large changes in enthalpy (ΔH = -112 kcal/mol) and entropy (ΔS = -384 cal/mol °K) accompany the activation process (n=9). The Q₁₀ calculated in the same temperature range is 23 (n=9). This thermodynamic analysis strongly suggests that the process of opening involves large conformational changes of the channel-forming protein. The highly temperature-dependent transition between open and closed configurations is thus possible because enthalpy and entropy are both large and compensate each other. Our results indicate that neither temperature nor voltage are strictly necessary for TRPM8 channel activation and that they can be understood in an allosteric voltage- and temperature-gating kinetic scheme.