The blood spinal cord barrier (BSCB) is essential for maintaining a regulated microenvironment for the spinal cord (SC) and its leakage is becoming more recognised as an important factor in SC dysfunction. BSCB impairment has been implicated in several diseases such as Amyotrophic lateral sclerosis (ALS), SC injury and ischaemia, Multiple sclerosis and Neuropathic pain. Using a new mouse model for cerebral cavernous malformation (CCM), a vascular disease of the central nervous system, we are exploring the involvement of BSCB disruption. We observed that CCM mouse spinal cord has increased haemorrhage, hemosiderin deposition and explored mast cell infiltration and tight junction (TJ) protein expression compared wild-type littermates. In addition, using a mouse model of cigarette smoking we have examined the detrimental effects cigarette smoke (CS) has on the BSCB in regard to ALS disease pathogenesis. By comparing CS-exposed mice to SOD1 controls we investigated TJ protein expression, hemosiderin deposition, mast cell infiltration and motor neuron density. Therefore, by investigating both ALS and CCM we have demonstrated the importance of BSCB impairment in SC dysfunction. We hope that these mouse models will provide new therapeutic targets and aid in the development of potential cure for various SC disorders.