Therapeutic plasma exchange (TPE) is widely used for various diseases, particularly in critically ill patients. Most of these indications rely mainly on the removal of pathological molecules in the plasma by TPE. TPE is also used to replace missing plasma components in some diseases. However, there are emerging data on the use of TPE in novel indications because of its potential immunomodulatory effects. This review discusses the techniques of TPE, key considerations when prescribing TPE, indications for TPE in critically ill patients, emerging developments and knowledge gaps in this field.