The pathogenesis of the slow virus encephalopathies and multiple sclerosis is reviewed within the framework of the immune response. The diseases are analyzed for the component of the immune response that appears to be crucial to the host's failure to control the disease. Thus, the absence of an immune response in the spongiform encephalopathies appears to reflect a failure of antigen recognition. Progressive multifocal leukoencephalopathy (PML), subacute sclerosing panencephalitis (SSPE), and progressive rubella panencephalitis (PRP) may result principally from a failure of effector mechanisms. In PML the failure usually occurs within the setting of an immunosuppressive illness. Conversely, in SSPE and PRP the effector failure seems to result from the nature of the host-virus interaction itself. Finally, evidence is accumulating that a defect of immunoregulation plays a significant role in multiple sclerosis.