Abstract: ALS is a fatal neurodegenerative disease leading to paralysis and eventual death within 3 to 5 years of diagnosis due to respiratory dysfunction. Numerous pathogenic intrinsic and extrinsic effectors are involved in the diffuse motor neuron degeneration. Also, impairment of neurovascular unit components in the brain and spinal cord in ALS patients and in animal models of disease was noted and points to vascular pathology being a key factor in the recognition of ALS as a neurovascular disease (Garbuzova-Davis et al., 2011). Our original (Garbuzova-Davis and Sanberg, 2014) and other studies (Winkler et al., 2014; Kakaroubas et al., 2019) provide convincing evidence on structural and functional alterations of the blood-CNS barrier (B-CNS-B) in ALS, potentially representing an additional pathogenic disease mechanism. Degeneration of endothelial cells (ECs) and astrocyte end-feet processes, reduced pericyte capillary coverage, dysfunction of tight junction proteins, and impairment of endothelial transport system have been shown to compromise B-CNS-B integrity. Vascular leakage and microhemorrhages were also noted in the spinal cord. The weakened barrier function may allow detrimental factors from the systemic circulation to penetrate the CNS and escalate motor neuron degeneration. Additionally, vascular pathologies in ALS were determined not only within, but also outside of the CNS. Recently, we showed damaged microvasculature in the lungs of G93ASOD1 mutant mice at the late stage of disease (Garbuzova-Davis et al., 2020). Numerous microhemorrhages, substantial capillary leakage and even capillary rupture resulting in lung petechiae, potentially via ECs damage, may represent essential effectors towards respiratory dysfunction in ALS. These findings are concurrent with noted capillary alterations within the CNS in both ALS patients and animal models of ALS. Since the damaged capillary endothelium in ALS does not properly maintain vascular homeostasis within and outside of the CNS, repairing the altered endothelium by cell administration may be a new therapeutic approach for this disease.