Inflammation in many autoimmune syndromes is modulated by the nervous system. This paper reviews important principles of neurogenic inflammation and findings of substance P overexpression in rheumatic diseases. Substance P is a key molecule in activating inflammation after antidromal axoplasmic transport and secretion at the nociceptor. We summarize the results from studies with rheumatoid arthritis, osteoarthritis, psoriatic arthritis, systemic lupus erythematodes, systemic sclerosis, vasculitides, Sjogren syndrome, vasculitides, reflex sympathetic dystrophy, gouty arthritis, fibromyalgia syndrome, chronic fatigue syndrome and degenerative vertebral spine disorders. Although substance P is associated with many of these diseases, selective receptor blockers have not been effective in therapy. In contrast, the nonselective antagonist capsaicin is beneficial in some conditions. We also discuss a novel therapeutic principle with selective serotonin antagonists that may induce a powerful downregulation of neurogenic inflammation.