The identification of compounds that can more effectively and safely treat both acute and chronic pain states and, additionally, show a reduced tendency to elicit the side effects associated with the use of morphine and its congeners remains a major unmet challenge in biomedical research. The recent identification of the cyclooxygenase 2 (COX-2) inhibitors,1,2 a novel class of compounds that has the antiinflammatory, analgesic, and antipyretic actions of the traditional nonsteroidal, antiinflammatory drugs (NSAIDs) such as aspirin (1) but lacks their limiting gastrointestinal side effects, will probably result in safer compounds for chronic use. However, the current COX-2 inhibitors appear unlikely to result in agents that will have any greater therapeutic efficacy than the NSAIDs.3 The discovery of the opioid receptor family and the endogenous opioids, the enkephalins and endorphins, in the early 1970s4 heralded the beginning of the molecular era of pain research. This was a major conceptual advance in identifying the receptors involved in mediating both the analgesic actions of the opioids and their side effects, e.g., addiction, gastric stasis, and respiratory depression. A premise implicit from this seminal research was that it would be relatively straightforward, using the then newly developed techniques of radioligand binding together with traditional medicinal chemistry approaches and molecular modeling, to develop novel ligands that selectively target opioid receptor subtypes. The resultant ligands would be anticipated to be novel analgesics that have the analgesic efficacy of morphine but lack its side effect liabilities. Despite an intensive research effort over the past two decades involving many innovative approaches in the global academic community and by the pharmaceutical industry, the latter representing an aggregate investment in excess of $2.5 billion, the only new opioid-based pain medications either in clinical development or on the market are alternative dosage forms of the classical opioids, morphine (2), loperamide (ADL-2-1294, 3), and fentanyl (4), or compounds such as tramadol (5).5 Continuing research advances in the understanding of the pharmacology of pain and analgesia that have resulted from the application of molecular biology techniques and the development of selective ligands for the various receptor classes involved in nociceptive transmission have established that pain is an extremely complex and dynamic process involving multiple, interrelated neurotransmitter/neuromodulator systems in the spinal cord, in ascending and descending spinal pathways, and at supraspinal sites. As Dray et al. have noted6 "not all pain states are created equal". In this Perspective, the incidence of pain, its types, and its mechanisms are reviewed in the context of the advances in understanding that have occurred in the past 20 years. This is followed by an overview of (i) the current trends in NSAID, opioid, and adjuvant analgesic research and (ii) newly identified molecular targets that are sites at which novel ligands may have analgesic potential and thus represent prototypes that will lead to novel, non-opioid, non-NSAID approaches to pain management early in the first decade of the 21st century.