Burn centers routinely treat a complex mix of patients with soft tissue injuries, including burn injuries, necrotizing soft tissue infections, and dermatologic conditions such as toxic epidermal necrolysis (TEN). In each of these conditions, fluid resuscitation, surgical interventions, and advances in critical care have improved survival significantly; however, there remains a subset of patients who do not respond to conventional means. It is because of these patients that we continue to seek means to “rescue” patients who are failing to respond to conventional care. Therapeutic plasma exchange (TPE) is an uncommon and underutilized treatment modality that has been used as a form of treatment “rescue.” We provide a review of the literature describing the use of TPE in TEN, burn shock, and sepsis. Our review of the literature over the past 30 years demonstrates persistent clinical benefits and reduced morbidity and mortality with use of TPE in TEN, burn shock, and sepsis. Many studies demonstrate significant improvement in morbidity and mortality with TPE in patients suffering from these conditions. However, future well-designed studies of the role of TPE in conditions commonly encountered in burn units are indicated. Improved awareness of TPE may lead to increased use of this uncommonly utilized modality and allow for potential future collaboration in a prospective, randomized, controlled trial with a larger number of subjects.