Motor or sensory activity in one arm can affect the other arm. We tested the hypothesis that a voluntary contraction can affect the motor pathway to the contralateral homologous muscle and investigated whether alterations in sensory input might mediate such effects. Responses to transcranial magnetic stimulation [motor-evoked potentials (MEPs)], stimulation of the descending tracts [cervicomedullary MEPs (CMEPs)], and peripheral nerve stimulation (H-reflex) were recorded from the relaxed right flexor carpi radialis (FCR), while the left arm underwent unilateral interventions (5 s duration) that included voluntary contraction, muscle contraction evoked through percutaneous stimulation, tendon vibration, and cutaneous and mixed nerve stimulation. During moderate to strong voluntary wrist flexion on the left, MEPs in the right FCR increased, CMEPs were unaffected, and the H-reflex was depressed. These results are consistent with an increase in excitability of the motor cortex, no effect on the motoneuron pool, and presynaptic inhibition of Ia afferents. In contrast, percutaneous muscle stimulation facilitated both MEPs and the H-reflex. However, muscle contraction produced by a combination of voluntary effort and electrical stimulation also reduced the contralateral H-reflex. After voluntary contractions, the H-reflex remained depressed for 35 s, but after stimulation-evoked contractions, it rapidly returned to baseline. Under both conditions, MEPs recovered rapidly. After voluntary contractions, CMEPs were also depressed for approximately 10 s despite their lack of change during contractions. Wrist tendon vibration (100 Hz) did not affect, and 20-Hz median nerve stimulation or forearm medial cutaneous nerve stimulation mildly facilitated, the H-reflex without affecting MEPs. Voluntary wrist extension, similarly to wrist flexion, increased MEPs and depressed H-reflexes. However, ankle dorsiflexion facilitated the H-reflex akin to the Jendrassik maneuver. These data suggest that a unilateral voluntary muscle contraction has contralateral effects at both cortical and segmental levels and that the segmental effects are not replicated by stimulated muscle contraction or by input from muscle spindles or non-nociceptive cutaneous afferents.