There has been a surge of interest and efforts towards modulating peripheral nerves, such as the vagus nerve, to treat various health conditions including tinnitus, rheumatoid arthritis, inflammatory bowel disease, depression and several other diseases. Unfortunately, there is limited understanding of the anatomical and functional organization of these peripheral pathways and their effects on different end-organs in healthy and diseased states. I will present recent results from my lab demonstrating the ability to use electrical and ultrasound stimulation to modulate the vagus nerve pathway and spleen to alter release of specific cytokines and biomolecules within the body, as well as reduce symptoms associated with rheumatoid arthritis in rodents. Ultrasound stimulation can enhance or suppress ongoing nerve activity depending on the selected parameters. These neuromodulatory effects may involve both thermal and mechanical mechanisms. Encouragingly, ultrasound stimulation could serve as a noninvasive method for modulating peripheral nerves and end-organs towards treatment of various diseases. Ultrasound stimulation could also be paired with electrical stimulation to achieve various modulatory and therapeutic effects. Further studies are needed to identify appropriate targets and stimulation patterns for different health conditions.