This review focuses on current approaches to understanding the immunopathogenesis of human T cell lymphotropic virus (HTLV) type I–associated myelopathy/tropical spastic paraparesis (HAM/TSP) based on newly developed molecular and immunologic techniques that have been adapted to studies of HTLV-I proviral load, HTLV-I mRNA, and HTLV-I tax-specific CD8 T cells. These methods enable researchers to study previously inaccessible aspects of this disease and allow a more detailed analysis of virus/host immune responses as they relate to disease specificity in this disorder. The role of HTLV-I–specific CD8 T cell immune responses is highlighted. The elucidation of the immunopathology of HAM/TSP will enhance our understanding of other HTLV-I–associated disorders plus other neurologic, hematologic, and inflammatory diseases for which viral etiologies have been suggested