The blood-brain barrier (BBB) is indispensable for the maintenance of brain homeostasis and proper neuronal functioning. Dysfunction of the BBB significantly contributes to the pathogenesis of neuroinflammatory and neurodegenerative diseases like stroke, multiple sclerosis (MS), and Alzheimer's disease (AD). The neuroinflammatory environment that characterizes these disorders propagates chronic impaired function of the BBB, processes that will be discussed in this review. Limiting dysfunction of the BBB may be an attractive target for treatment of neurological disorders. To date, no current treatments are directly targeting the function of the BBB. In this review, we will specifically discuss the potential protective role of nuclear liver X receptors (LXRs) as a promising therapeutic target to reverse or prevent BBB impairment in neurological diseases.