For diverse reasons ranging from needing better brain mapping tools to treating pervasive brain diseases, there are needs for improved methods of modulating human brain activity. Since ultrasound can produce mechanically driven changes in cellular signaling and since it can be readily transmitted and focused through skin and skull bone, I established and led research efforts concentrated on engineering novel neuromodulation methods using pulsed ultrasound. This seminar will provide a general overview of our experiences while outlining fundamental observations that pulsed ultrasound can noninvasively modulate the activity of brain slices, in vivo brain circuits of rodents, and deep-brain nuclei in non-human primates. A more in depth discussion will provide added insight into our recent observations that transcranial focused ultrasound can modulate human brain activity in cortical circuits while conferring a spatial resolution approximately five times better than transcranial magnetic stimulation. With respect to the biophysical mechanisms of action, we have studied and will discuss our observations related to the mechanical influence of pulsed ultrasound on the activity of single ion channels and changes in the tension of lipid membranes. Our current efforts in developing ultrasonic neuromodulation for use in the MR-environment will be briefly described. Finally, it will be summarized how ultrasonic neuromodulation lends itself to the design of human-machine interfaces where interacting with the brain to encode or modulate information processing is a goal.