Membrane voltage, ligand binding, mechanical force and temperature can all induce conformational changes that open ion channel pores. A key question in understanding ion channel function is how the protein domains involved in sensing stimuli (sensors) communicate with the pore to gate its opening and closing. TRP channels are considered six-transmembrane cation-permeable channels, distant relatives of voltage-gated potassium channels (Kv), which are known to be activated by membrane depolarization. Understanding the molecular nature of thermo-TRP channel gating offers a fair challenge to biophysicists. This chapter will summarize our present knowledge on the effect of voltage and temperature during thermo-TRP channel activation.