Lateralization of motor control refers to the ability to produce pure unilateral or asymmetric movements. It is required for a variety of coordinated activities, including skilled bimanual tasks and locomotion. Here we discuss the neuroanatomical substrates and pathophysiological underpinnings of lateralized motor outputs. Significant breakthroughs have been made in the past few years by studying the two known conditions characterized by the inability to properly produce unilateral or asymmetric movements, namely human patients with congenital “mirror movements” and model rodents with a “hopping gait”. Whereas mirror movements are associated with altered interhemispheric connectivity and abnormal corticospinal projections, abnormal spinal cord interneurons trajectory is responsible for the “hopping gait”. Proper commissural axon guidance is a critical requirement for these mechanisms. Interestingly, the analysis of these two conditions reveals that the production of asymmetric movements involves similar anatomical and functional requirements but in two different structures: (i) lateralized activation of the brain or spinal cord through contralateral silencing by cross-midline inhibition; and (ii) unilateral transmission of this activation, resulting in lateralized motor output.