Achieving adequate but not excessive sedation in critically ill, mechanically ventilated patients is a complex process. Analgesics and sedatives employed in this context are extremely potent, and drug requirements and metabolism are unpredictable. Clinicians must have heightened awareness of the potential for enduring effects and are encouraged to employ strategies that maximize benefit while minimizing risk. Successful sedation protocols have three basic components: frequent assessments for pain, anxiety, and agitation using a reproducible scale; combination therapy coupling opioids and sedatives; and, most importantly, careful communication between team members, with a particular recognition that the bedside nurse must be empowered to pair assessments with drug manipulation. In recent years, two broad categories of sedation protocols have achieved clinical success in terms of decreasing duration of mechanical ventilation and intensive care unit length of stay by minimizing drug accumulation. Patient-targeted sedation protocols (the first category) rely on structured assessments to guide a careful schema of titrated drug escalation and withdrawal. Variation exists in the assessment tool utilized, but the optimal goal in all strategies is a patient who is awake and can be readily examined. Alternatively, daily interruption of continuous sedative infusions (the second category) may be employed to focus care providers on the goal of achieving a period of awakening in the earliest phases of critical illness possible. Newer literature has focused on the safety of this strategy and its comparison with intermittent drug administration. Ongoing investigations are evaluating the broad applicability of these types of protocols, and currently one may only speculate on whether one strategy is superior to another.