Morphine is the preferred analgesic agent for the critically ill patient. Fentanyl is the preferred analgesic agent for critically ill patients with hemodynamic instability or for patients manifesting symptoms of histamine release with morphine or morphine allergy. Hydromorphone is an acceptable alternative to morphine for patients with significant adverse affects from morphine or severe renal dysfunction. Meperidine and intravenous codeine should be avoided if at all possible. APAP and NSAIDs may be useful in the management of acute pain secondary to their opioid-sparing effects. Use of nonopioid analgesics may reduce the dose of opioid required for adequate pain control and help to minimize opioid-induced side effects. NSAIDs should be used only when the benefit-to-risk ratio is favorable. APAP should be used as an adjunct but not as the sole analgesic agent in critically ill patients. Regardless of which agent or agents are used to optimize pain control, it is imperative that caregivers recognize that the optimal analgesic dose and regimen vary widely between patients. Based on the pharmacokinetics and pharmacodynamics of the agent(s) selected, enough time for an adequate trial should be allowed before switching to other agents. Employing these principles optimizes the use of medications in the management of the complex physiologic response to pain.