Photopheresis, a leukapheresis-based therapy that combines 8-methoxypsoralen (8-MOP) and ultraviolet-A irradiation, has been shown to be an effective treatment for advanced cutaneous T cell lymphoma (CTCL), but also appears to be effective in certain patients with systemic sclerosis (SSc) and chronic graft versus host disease (cGVHD). In CTCL, clinical responsiveness to photopheresis has been shown to be dependent on the presence of detectable circulating clonal T cells in peripheral blood. Herein we review recent work from our group demonstrating that circulating clonal populations of T cells are detectable in a subgroup of patients with SSc and cGVHD. Furthermore, we provide initial evidence that the presence of a T cell clone in such patients may be associated with responsiveness to photopheresis.