Importance: Handedness and motor asymmetry are important features of occupational performance. With an increased understanding of the basic neural mechanisms surrounding handedness, clinicians will be better able to implement targeted, evidence-based neurorehabilitation interventions to promote functional independence. Objective: To review the basic neural mechanisms behind handedness and their implications for central and peripheral nervous system injury. Data Sources: Relevant published literature obtained via MEDLINE. Findings: Handedness, along with performance asymmetries observed between the dominant and nondominant hands, may be due to hemispheric specializations for motor control. These specializations contribute to predictable motor control deficits that are dependent on which hemisphere or limb has been affected. Clinical practice recommendations for occupational therapists and other rehabilitation specialists are presented. Conclusions and Relevance: It is vital that occupational therapists and other rehabilitation specialists consider handedness and hemispheric lateralization during evaluation and treatment. With an increased understanding of the basic neural mechanisms surrounding handedness, clinicians will be better able to implement targeted, evidence-based neurorehabilitation interventions to promote functional independence. Plain-Language Summary: The goal of this narrative review is to increase clinicians’ understanding of the basic neural mechanisms related to handedness (the tendency to select one hand over the other for specific tasks) and their implications for central and peripheral nervous system injury and rehabilitation. An enhanced understanding of these mechanisms may allow clinicians to better tailor neurorehabilitation interventions to address motor deficits and promote functional independence. This rapid review examines the basic neural mechanisms behind handedness and their implications for central and peripheral nervous system injury and rehabilitation.