Assessing pain and sedation in nonresponsive patients is challenging. A major challenge is the confounding effect of sedation on objective indicators of pain. Clinicians might infer that adequate sedation means different patient states: promotion of amnesia, sleep/rest, patient safety, ventilator synchrony, and hemodynamic stability. Hence, an ideal measure that can adequately address the complexity and individualize the nature of the goals of pain and sedation therapy remains elusive. Furthermore, the behavioral responses to pain and anxiety/agitation (eg, restlessness, ventilator dyssynchrony, and movement) have many similarities. Tolerance to mechanical ventilation has been suggested to have validity in both an ICU pain scale and a sedation scale. Additional research is needed to establish the validity, sensitivity, and specificity of these pain indicators in sedated patients. In the meantime, in circumstances where patients are nonresponsive to external stimuli, clinicians should integrate other information such as actual or potential risks of pain (eg, extensiveness of injury, invasive therapies, intubation) and risks of pain-related functional impairment into their pain assessment in nonresponsive, sedated patients.