This article discusses the rationale of sedation in respiratory failure, sedation goals, how to assess the need for sedation as well as effectiveness of interventions in critically ill children, with validated observational sedation scales. The drugs and non-pharmacological approaches used for optimal sedation in ventilated children are reviewed, and specifically the rationale for drug selection, including short- and long-term efficacy and safety aspects of the selected drugs. The specific pharmacokinetic and pharmacodynamic aspects of sedative drugs in the critically ill child and consequences for dosing are presented. Furthermore, we discuss different sedation strategies and their adverse events, such as iatrogenic withdrawal syndrome and delirium. These principles can guide clinicians in the choice of sedative drugs in pediatric respiratory failure.