Fourteen neurologically healthy, right-handed subjects performed a choice-hand reaction time (RT) task, which involved wrist flexion or extension of either the left or right hand to one of three fixed target locations corresponding to 45 degrees flexion, 20 degrees flexion, or 20 degrees extension from the starting position. In each trial, a pre-cue provided information regarding the forthcoming target location. The hand was specified by the imperative signal. Focal transcranial magnetic stimulation (TMS) was delivered over the hand motor area of either the right or left hemisphere at set times during the foreperiod, and at random intervals during the RT interval defined by electromyography onset. As expected, an increase in corticomotor excitability was observed in the agonist of the responding hand over the RT interval. When the cue appeared at a location that required flexion with either hand, an increase in excitability was observed following stimulation over the hemisphere ipsilateral to the responding hand, indicating activation of the homologous muscle. However, when the cue appeared at a location at which the response would require flexion with one hand and extension with the other, the modulation of excitability was also based on the direction of the response. This direction-specific effect was only observed for TMS delivered to the left hemisphere during the left-hand movement, and suggested goal-based preparation in the left hemisphere independent of whether the actual movement is made with the right or left hand. These results indicate that both the homologous-muscle and the directional-specific constraints affect the corticomotor excitability of the non-responding hand.