Therapeutic plasma exchange is an extracorporeal plasmapheresis method for removing high-molecular-weight pathogens and toxins from the circulation. It can be indicated in many clinical conditions, both kidney-related and non-kidney-related. This review focuses on clinical trials related to Goodpasture syndrome, thrombotic thrombocytopenic purpura, and acute renal insufficiency due to multiple myeloma. It also discusses the difficulties and opportunities associated with the development of a randomized controlled multicenter study and of a web-based database. Finally, we report a summary of the risks and complications of therapeutic plasma exchange and how we can update the information on their frequency and seriousness by means of a longitudinal prospective multicenter study open to all centers performing the procedure.