Pain is the most common reason for consultation with a physician, but because pain is not objectively measurable, it is often neglected or underestimated. Chronic, severe pain is a major complication of cancer and HIV-1 infection. Current therapy typically employs stepwise treatment first with nonopioid analgesics, followed by weak and then strong opioids. Nevertheless, treatment can be limited both by side effects and by the development of tolerance, and patients with neuropathic pain are often resistant to all conventional therapies. Much has been learned about the neuroanatomy and physiology of both acute and chronic pain. Drugs now being developed, such as alpha(2)-receptor agonists, the N-type calcium channel blocker, SNX-111 and NMDA antagonists, take advantage of current knowledge of the neurochemistry of pain transduction and target neurotransmitter modulation as a means of achieving analgesia. These new drugs and alternative administration methods, such as intraspinal drug delivery and preemptive analgesia for postoperative pain, should add substantially to the current analgesic armamentarium.