1. We used transcranial magnetic stimulation (TMS) to study the role of plastic changes of the human motor system in the acquisition of new fine motor skills. We mapped the cortical motor areas targeting the contralateral long finger flexor and extensor muscles in subjects learning a one-handed, five-finger exercise on the piano. In a second experiment, we studied the different effects of mental and physical practice of the same five-finger exercise on the modulation of the cortical motor areas targeting muscles involved in the task. 2. Over the course of 5 days, as subjects learned the one-handed, five-finger exercise through daily 2-h manual practice sessions, the cortical motor areas targeting the long finger flexor and extensor muscles enlarged, and their activation threshold decreased. Such changes were limited to the cortical representation of the hand used in the exercise. No changes of cortical motor outputs occurred in control subjects who underwent daily TMS mapping but did not practice on the piano at all (control group 1). 3. We studied the effect of increased hand use without specific skill learning in subjects who played the piano at will for 2 h each day using only the right hand but who were not taught the five-finger exercise (control group 2) and who did not practice any specific task. In these control subjects, the changes in cortical motor outputs were similar but significantly less prominent than in those occurring in the test subjects, who learned the new skill.(ABSTRACT TRUNCATED AT 250 WORDS)