We review the effects of CD40 signaling in traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, and brain tumors, and highlight recent therapeutic advancements targeting the CD40–CD40L system. This evidence concerns the gene CD40 and early-onset autosomal dominant Alzheimer disease.