Large Granular Lymphocytic Leukemia (LGLL) is a rare lymphoproliferative disorder of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells with chronic and ill-defined clinical progression. Presentation at diagnosis can include asymptomatic or symptomatic cytopenias, recurrent infections, splenomegaly and rheumatoid arthritis. Multiple cell survival pathways are involved in the pathogenesis of LGLL, and it has been found to be specifically associated with aberrant STAT3 signaling. An increased number of clonal LGL cells in the blood establishes the diagnosis. Treatment regimens historically have included cyclophosphamide, methotrexate, steroids, cyclosporine, and splenectomy, but there are no available targeted therapies or definitive cure available for LGLL. Here we present three cases with varying treatment responses and outcomes that highlight the need for targeted therapy development. All three patients were confirmed to have T-LGLL by flow cytometry analysis. Patient one is a 64 year old female, presented for moderate recurrent symptoms of LGLL, initially diagnosed 17 years prior and treated with 6 months of cyclophosphamide. On the second presentation she was found to have STAT3 missense mutation and was treated for a second time with cyclophosphamide which improved symptoms. She additionally required subcutaneous immunoglobulin for treatment of recurrent infection. Patient two is a 72 year old male, presented for recurrent aphthous ulcers with severe leukopenia and neutropenia, found to have STAT3 negative LGLL. He received multiple courses of cyclophosphamide and was refractory to treatment with persistent symptoms despite improvement in leukopenia. Patient three is a 70 year old male, presented for symptomatic lymphocytosis. He was found on flow cytometry to have LGLL. He improved without further testing or treatment and has remained in remission for several years. These cases show the variation in presentation and response to therapy for patients with T-LGLL. Previous research has demonstrated the heterogeneity of LGLL and has additionally shown that STAT3 mutation was associated with decreased overall survival. This may be as yet simplifying the pathogenesis for targeting as we can still see heterogeneous clinical response even within STAT3 positive patients. One study showed that the size of the mutated clone correlated with degree of clonal expansion and that immunosuppressive therapy may not be able to reduce the clonal burden at high degrees of mutation. Our cases show that STAT3 positive status is not enough to determine prognosis and treatment course. The degree and types of mutation may need to be quantified as well as additional targets identified. While pursuing targeted treatment therapies for LGLL we must also pursue testing to assess disease burden.