Pain is a multidimensional, complex experience. Critically ill patients are particularly vulnerable to pain. Patients in a critical care environment often have difficulty communicating their pain, and their pain may be aggravated by fear and anxiety. Indeed, their response to pain may compromise recovery. Although the significance of pain has been cited in literature, there is a dearth of research regarding pain in the critically ill. Such future research, as well as practice interventions, should be based on an understanding of pain psychophysiology. This article presents an in-depth review of pain mechanisms, including a discussion of pain modulation by the endogenous opioid system. Also reviewed are various pain theories contributing to our knowledge of pain. Finally, methods of pain measurement and treatment are outlined, and their appropriateness to critical care is evaluated. Although knowledge about pain mechanisms, measurement, and therapies has expanded, many issues remain unexplained. This article poses questions regarding pain in critically ill patients and presents specific areas for future nursing research.