The modern therapy of the pain of inflammatory rheumatic disease and osteoarthritis is based on several advances in molecular biology, which are reviewed in this paper. Inhibition of the ubiquitous enzyme cyclooxygenase by the nonsteroidal anti-inflammatory drugs including the salicylates prevents the production of endoperoxides, which are pro-inflammatory, and prostaglandins E2 and I2, which sensitize peripheral pain receptors. In addition, a fundamental understanding of neural tracts that inhibit the pain signal has introduced the concept of giving low dose tricyclic antidepressants for chronic pain to block the re-uptake of serotonin from the neural cleft of synapses. This amplifies the effect of serotonin and catecholamines, which are neurotransmitters for these inhibitory tracts.