Clonal lymphoproliferative diseases of large granular lymphocytes (LGL) arise from both CD3-negative and CD3-positive cells, which define NK and T-LGL leukemia, respectively. Chronic neutropenia and anemia represent the most common clinical manifestation of these diseases but lymphocyte infiltration into bone marrow, spleen, and liver also occurs in some cases. The mechanism(s) responsible for expansion of the LGLs are unknown and the impact of lymphocytosis on the development of cytopenias is also incompletely defined. In this review, we discuss the incidence, clinical presentation, diagnostic criteria, and possible mechanisms of LGL leukemia pathogenesis. Despite the indolence of most cases of LGL leukemia, approximately 65% of patients will require therapy. There have been few controlled clinical trials conducted in this disease and long-term treatment is often required for sustained disease control. Novel therapies are primarily directed toward the targeted disruption of LGL leukemia survival. Conventional and novel therapeutics are discussed.