Technological development and an explosion of interest in non-invasive brain stimulation over the past 30 years have led to new insights into human brain function, pathophysiology, and plasticity. The number of present applications is astounding, and has proceeded faster than a firm grasp of mechanism. Although the basis of this approach stems from work in the motor system, it has also been shown to have potential benefit in cognitive processes and psychiatric diseases. As data emerge concerning performance enhancement in healthy humans, new questions arise, including ethical considerations. This chapter discusses the development of brain stimulation and neuromodulation as remarkable tools of the twenty-first century for understanding and promoting human brain plasticity. The present limitations and future directions of the field are also discussed.