Paraneoplastic cerebellar degeneration is an uncommon autoimmune disorder characterized clinically by progressive, ultimately incapacitating ataxia and pathologically by destruction of cerebellar Purkinje cells, with variable loss of other cell populations. The disorder is most commonly associated with gynecological and breast carcinomas, small cell carcinoma of the lung, and Hodgkin's disease and in most cases comes on prior to identification of the underlying neoplasm. The hallmark of paraneoplastic cerebellar degeneration is the presence of an immune response reactive with intracellular proteins of Purkinje or other neurons or, less commonly, against neuronal surface antigens. Evidence-based treatment strategies for paraneoplastic cerebellar degeneration do not exist; and approaches to therapy are thus speculative. Diagnosis and treatment of the underlying neoplasm is critical, and characterization of the antibody response involved may assist in tumor diagnosis. Most investigators have initiated treatment with corticosteroids, plasma exchange, or intravenous immunoglobulin G. Cyclophosphamide, tacrolimus, rituximab, or possibly mycophenolate mofetil may warrant consideration in patients who fail to stabilize or improve on less aggressive therapies. Plasma exchange has been of questionable benefit when used alone but should be considered at initiation of treatment to achieve rapid lowering of circulating paraneoplastic autoantibodies. Because the course of illness is one of relentless neuronal destruction, time is of the essence in initiating treatment. Likelihood of clinical improvement in patients with longstanding symptoms and extensive neuronal loss is poor.