Transcranial focused ultrasound (US) has been demonstrated to stimulate neurons in animals and humans, but the mechanism of this effect is unknown. It has been hypothesized that US, a mechanical stimulus, may mediate cellular discharge by activating mechanosensitive ion channels embedded within cellular membranes. To test this hypothesis, we expressed potassium and sodium mechanosensitive ion channels (channels of the two-pore-domain potassium family (K2P) including TREK-1, TREK-2, TRAAK; Na V 1.5) in the Xenopus oocyte system. Focused US (10 MHz, 0.3-4.9 W/cm2) modulated the currents flowing through the ion channels on average by up to 23%, depending on channel and stimulus intensity. The effects were reversible upon repeated stimulation and were abolished when a channel blocker (ranolazine to block Na V 1.5, BaCl 2 to block K2P channels) was applied to the solution. These data reveal at the single cell level that focused US modulates the activity of specific ion channels to mediate transmembrane currents. These findings open doors to investigations of the effects ofUS on ion channels expressed in neurons, retinal cells, or cardiac cells, which may lead to important medical applications. The findings may also pave the way to the development of sonogenetics: A non-invasive, US-based analogue of optogenetics.