K2P potassium channels display constant conductance in the physiological membrane potential range and their activity is highly regulated by both chemical and physical modulators. K2P channels' activity affects numerous physiological processes such as cardiac function, pain perception, depression, neuroprotection and cancer development. Terpenes are a large family of compounds, mostly produced in plants. Several monoterpenes were found to affect the activity of a variety of ion channels. To date, the effect of terpenes on K2P channels has not been studied. Human K2P channels were expressed in Xenopus oocytes and currents were measured using the two-electrode voltage clamp technique. Channels' activity was found to be highly affected by monoterpenes. The currents of K2P2.1, and other mechanosensitive K2P channels, were enhanced several fold by carvacrol, thymol and menthol. K2P2.1 currents were decreased twofold by eugenol. The effect of monoterpenes was not limited to the known stretch-activated K2P channels, as K2P5.1 and K2P18.1 currents were also elevated by up to 15- fold by carvacrol. Currents of K2P3.1 and K2P9.1 were twofold decreased by the same substance. Cinnamaldehyde elevated K2P5.1 currents, but decreased K2P18.1 currents. The influence on K2P2.1 currents was indifferent to the phosphorylation state of the channel, and was mediated by a novel domain at the C-terminus, which contains a three arginines sequence. Our results demonstrate, for the first time, that terpenes might serve as powerful modulators of K2P channels, and that the mechanism of action involves the C-terminus regulatory domain.