Therapeutic plasma exchange is an apheresis modality in which plasma is separated from the blood cellular components ex vivo, discarded, and replaced with an isosmotic fluid (most commonly 5% albumin) to maintain appropriate oncotic pressure in the patient. Therapeutic plasma exchange is used in the treatment of many diseases and indications. The recent seventh edition of the American Society for Apheresis guidelines indicates approximately 72 diseases and 116 indications for which therapeutic plasma exchange may be effective. One of the critical aspects for the successful performance of therapeutic plasma exchange is appropriate vascular access to provide high blood flow for the collection and return phases of the procedure, especially because most patients who need therapeutic plasma exchange will require more than one treatment over days to weeks. This article provides an overview of the characteristics of therapeutic plasma exchange, the clinical diseases and indications that may be treated with therapeutic plasma exchange, and the different types of vascular access employed, with their advantages and disadvantages. The latter may include peripheral venous access and intravascular or implantable access devices, such as arteriovenous grafts and fistulas, central venous catheters, and central venous catheters tunneled with ports.