Stroke remains the leading cause of long-term disability. Hemiparesis is one of the most common post-stroke motor deficits and is largely attributed to loss or disruption of the motor signals from the affected motor cortex. As the only direct descending motor pathway, the corticospinal tract (CST) is the primary pathway to innervate spinal motor neurons, and thus, forms the neuroanatomical basis to control the peripheral muscles for voluntary movements. Here, we review evidence from both experimental animals and stroke patients, regarding CST axonal damage, functional contribution of CST axonal integrity and remodeling to neurological recovery, and therapeutic approaches aimed to enhance CST axonal remodeling after stroke. The new insights gleaned from preclinical and clinical studies may encourage the development of more rational therapeutics with a strategy targeted to promote axonal rewiring for corticospinal innervation, which will significantly impact the current clinical needs of subacute and chronic stroke treatment.