Since the late 1960s, air-fluidized therapy (AFT) has been effectively used to treat patients with pressure ulcers, burns, and many other clinical problems. Much of the demonstrated efficacy is believed to be associated with the unique fluid environment provided by AFT that is fundamentally different from the support provided by surfaces made up of conventional solid materials. Fluid support maximizes the envelopment of the body while significantly reducing shear, friction, and pressure, and mechanical stress applied to the skin and subcutaneous tissue. Additionally, the variable temperature airflow allows the microclimate to be controlled according to needs for both therapy and patient comfort. Clinical benefits of AFT include faster and more cost-effective healing of pressure ulcers, a decreased rate of hospitalizations and emergency room visits for long-term care pressure ulcer patients, decreased mortality of patients with extensive burns and inhalation injury and rapid healing and increased comfort in burn patients. The fluid support also results in a substantial decrease in the amount of caregiver effort required for repositioning patients and increased patient comfort in patients with multiple trauma and external fixation devices or deformities that require a conforming bed, and patients with cancer and bony metastasis. This article seeks to evaluate the physical differences in AFT over other mattress types and to review the published literature for this therapy modality.