Sedation, analgesia, and muscle relaxants are an integral part of critical care unit, which works like a double-edge sword, and hence judicious use of each agent remains the matter of primary concern. These get more compounded, especially when the patient is on extracorporeal therapy. The patient who needs extracorporeal therapies besides being critically ill also has altered pharmacokinetics for varied reasons and usually has longer ICU stay. Recently, there is a paradigm shift in practice of sedation in critical care unit from deep and prolonged sedation to short and minimal sedation. The basic goal of sedation therapy in a critical care unit is to keep the patient comfortable with minimal possible sedation, avoid muscle relaxants as far as possible, and try to give sedation break. The commonly used drugs are opioids, benzodiazepines, major tranquilizers, and anesthetic agents like barbiturates, propofol, etc. Ideal sedative agents during ECLS should be short-acting as daily sedation break is mandatory to assess CNS status, should not be reacting to the circuit (like fentanyl and propofol), and cardiostable. Extracorporeal circuits alter the pharmacokinetics of sedative agents by increase in the volume of distribution, circuit adsorption, and hypoproteinemia secondary to systemic inflammatory response syndrome (SIRS). The need for sedation in cardiac ECMO is very limited, provided there is no associated lung pathology (like pulmonary edema). Cardiac patient can well be kept off the ventilator, or if already intubated, can be extubated at the earliest so that the sedation requirement is minimized. In respiratory ECMO, invariable sedation is required, especially in the first few days till the time the patient stabilizes. Sedation requirement after 48 hours of ECMO is mostly because of patient-ventilator asynchrony and the air hunger. This can be to some extent managed by maintaining low PCO₂ (less than 30), which can be achieved by keeping high-sweep gas. The different scoring systems that can be followed are modified motor activity assessment scale (MMAAS) and Richmond agitation-sedation scale and comfort score. The monitoring scale is as per the institutional protocol. In contrast to the sedated patient, the awake patient has multiple advantages on medical, psychological, and social front.