The acquisition of a new motor skill is characterized first by a short-term, fast learning stage in which performance improves rapidly, and subsequently by a long-term, slower learning stage in which additional performance gains are incremental. Previous functional imaging studies have suggested that distinct brain networks mediate these two stages of learning, but direct comparisons using the same task have not been performed. Here we used a task in which subjects learn to track a continuous 8-s sequence demanding variable isometric force development between the fingers and thumb of the dominant, right hand. Learning-associated changes in brain activation were characterized using functional MRI (fMRI) during short-term learning of a novel sequence, during short-term learning after prior, brief exposure to the sequence, and over long-term (3 wk) training in the task. Short-term learning was associated with decreases in activity in the dorsolateral prefrontal, anterior cingulate, posterior parietal, primary motor, and cerebellar cortex, and with increased activation in the right cerebellar dentate nucleus, the left putamen, and left thalamus. Prefrontal, parietal, and cerebellar cortical changes were not apparent with short-term learning after prior exposure to the sequence. With long-term learning, increases in activity were found in the left primary somatosensory and motor cortex and in the right putamen. Our observations extend previous work suggesting that distinguishable networks are recruited during the different phases of motor learning. While short-term motor skill learning seems associated primarily with activation in a cortical network specific for the learned movements, long-term learning involves increased activation of a bihemispheric cortical-subcortical network in a pattern suggesting "plastic" development of new representations for both motor output and somatosensory afferent information.