Large granular lymphocyte (LGL) syndrome includes a spectrum of clonal T cell and natural killer cell chronic lymphoproliferative disorders. These conditions are thought to arise from chronic antigenic stimulation, while the long-term survival of the abnormal LGLs appears to be sustained by resistance to apoptosis and/or impaired survival signaling. T-cell LGL (T-LGL) leukemia is the most common LGL disorder in the Western world. Despite its indolent course, the disease is often associated with neutropenia, the pathogenesis of which is multifactorial, comprising both humoral and cytotoxic mechanisms. This article addresses the pathogenesis of T-LGL leukemia and natural killer cell chronic lymphoproliferative disorder, as well as that of T-LGL leukemia-associated neutropenia. Furthermore, as symptomatic neutropenia represents an indication for initiating treatment, available therapeutic options are also discussed.