Aging-related diseases including different kinds of dementia or cognitive impairment due to Alzheimer, Parkinson, multiple sclerosis (MS), stroke, or human immunodeficiency virus (HIV) are major public health problems. Despite the efforts and investment into new treatments and to understand the mechanisms of central nervous system (CNS) disease, the cellular and molecular basis of HIV CNS dysfunction is still poorly understood. Only recently, our group identified pannexin-1 channels as a key protein mediating CNS disease. Pannexin-1 channels are unique large ionic channels that allow the exchange of large signaling molecules between the cytoplasm and the extracellular space, including ATP and prostaglandins. Under physiological conditions, pannexin-1 channels are in a closed state that impedes intracellular ATP release and subsequent activation of ATP receptors. Only in pathogenic conditions such as ischemia/reperfusion, stroke, MS, and HIV these channels become open to further enhance inflammation and damage. Thus, pannexin-1 channels are unique pharmacological targets to reduce/prevent the devastating consequences of CNS diseases. Furthermore, our preliminary data indicate that the opening of pannexin-1 channels results in the secretion of several inflammatory factors that could affect the brain, including ATP and PGE2. Thus, serum concentration of ATP may serve as a biomarker of cognitive impairment in several CNS diseases. Interestingly, we found that specific pannexin-1 polymorphisms in different ethnic groups are associated with their differential susceptibility to CNS disease. Together, these observations have led us to formulate the hypothesis that pannexin-1 channels and the product released upon opening of the channel facilitate CNS disease in a range of CNS diseases. We truly believe that our unique interdisciplinary approach will help develop alternative therapeutic interventions to reduce the devastating consequences of Alzheimer, Parkinson, MS, stroke, or HIV.