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Opioid analgesics are commonly administered to hospitalized patients to treat acute pain, but these drugs put patients at risk for serious adverse events, such as unintended advancing sedation, respiratory depression, and death. Nurses play an important role in keeping patients safe by making clinical decisions about the frequency and intensity with which patients receiving IV and epidural opioids should be monitored. To make sound clinical judgments, nurses must be aware of the factors that place patients at elevated risk for adverse opioid-related effects and know how to screen and assess patients for these risks. The authors review the literature on unintended advancing sedation and respiratory depression associated with opioid administration and present evidence-based recommendations for clinical decision making and patient monitoring, using both nursing assessments and electronic technologies.