Considerable work has been carried out over the past 25 years to define the conditions for application of plasmapheresis or plasma exchange. The use of plasma exchange in neurologic disorders such as Guillain-Barré syndrome has seen widespread application including the combination of plasma exchange with the use of intravenous immunoglobulin. Investigators have assessed the use of each therapy alone and in combination and, although both are advantageous, the relative benefits of each are still somewhat unclear. Other forms of neuropathies also seem to benefit from plasma exchange, as do some vasculitides. The use of cryosupernatant rather than frozen plasma to treat thrombotic thrombocytopenic purpura has improved outcome, but the cumulative data from many trials indicate that the mortality rate, if anything, persists at an even higher level than it did decades ago. Hemolysis, elevated liver enzymes, and low platelets syndrome, which has some characteristics similar to those of thrombotic thrombocytopenic purpura, has been shown to have variable response to plasma exchange. Plasma exchange has also been assessed as a treatment in organ failure and transplant rejection. Liver failure has shown variable response even when bioartificial livers are used. Of particular interest is the emerging use of photopheresis as an immune modulatory therapy. This is one of the newer innovative modifications of standard plasma exchange that will undoubtedly lead to interesting future therapeutic opportunities. The field continues to evolve.