Large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of either CD3(+) cytotoxic T or CD3(-) NK cells. Prominent clinical features of T-LGL leukemia include neutropenia, anemia and rheumatoid arthritis (RA). The terminal effector memory phenotype (CD3(+)/CD45RA(+)/CD62L(-)CD57(+)) of T-LGL suggests a pivotal chronic antigen-driven immune response. LGL survival is then promoted by platelet-derived growth factor and interleukin-15, resulting in global dysregulation of apoptosis and resistance to normal pathways of activation-induced cell death. These pathogenic features explain why treatment of T-LGL leukemia is based on immunosuppressive therapy. The majority of these patients eventually need treatment because of severe or symptomatic neutropenia, anemia, or RA. No standard therapy has been established because of the absence of large prospective trials. The authors use low-dose methotrexate initially for T-LGL leukemia patients with neutropenia and/or RA. We recommend either methotrexate or oral cyclophosphamide as initial therapy for anemia. If treatment is not successful, patients are switched to either the other agent or cyclosporine. The majority of patients experience an indolent clinical course. Deaths infrequently occur because of infections related to severe neutropenia. As there are no curative therapeutic modalities for T-LGL leukemia, new treatment options are needed.