BACKGROUND AND PURPOSE Crossing pathologies of the corticospinal tract (CST) are rare and often associated with genetic disorders. However, they can be present in healthy humans and lead to ipsilateral motor deficits when a lesion to motor areas occurs. Here, we review historical and current literature of CST crossing pathologies and present a rare case of asymmetric crossing of the CST. METHODS Description of the case and systematic review of the literature were based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed database was searched for peer-reviewed articles in English since 1950. All articles on ipsilateral stroke, uncrossed CST, and associated neurologic disorders were screened. Furthermore, a literature review between the years 1850 and 1980 including articles in other languages, books, opinions, and case studies was conducted. RESULTS Only a few descriptions of CST crossing pathologies exist in healthy humans, whereas they seem to be more common in genetic disorders such as horizontal gaze palsy with progressive scoliosis or congenital mirror movements. Our patient presented with aphasia and left-sided hemiparesis. Computed tomographic (CT) scan revealed a perfusion deficit in the left middle cerebral artery territory, which was confirmed by diffusion-weighted magnetic resonance imaging (MRI), so that thrombolysis was administered. Diffusion tensor imaging with fibre tracking revealed an asymmetric CST crossing. CONCLUSIONS The knowledge of CST crossing pathologies is essential if a motor deficit occurs ipsilateral to the lesion side. An ipsilateral deficit should not lead to exclusion or delay of therapeutic options in patients with suspected stroke. Here, a combined evaluation of CT perfusion imaging and MRI diffusion imaging may be of advantage.