OBJECTIVE An increased number of granular lymphocytes (GL) has been reported in various clinical conditions and is currently interpreted as a reactive process to an underlying antigen stimulation. In recent years, a disease characterized by a definite increase in granular lymphocytes has been identified and recognized as lymphoproliferative disease of GL (LDGL). The aim of this study is to review the clinical, biological and pathogenetic mechanisms leading to this disorder. METHODS Criteria for the diagnosis, immunologic and molecular evaluation, clinical features and new therapeutic approaches are reviewed. RESULTS More than 500 patients have been adequately reported in the literature. Immunologic classification of this disease distinguishes a CD3+ form which is more common, and a CD3- variant; this latter accounting for nearly 15% of LDGL cases. CD3+ LDGL is symptomatic in approximately 50% of cases, neutropenia, infections and anemia being the most frequent findings. Clonality of the T-cell receptor is usually documented in these patients. Cytokines such as IL-2, IL-12 and IL-15 have been claimed to play a role in this disorder. Symptomatic patients may benefit from combination therapy with low dose methotrexate and steroids. CD3- LDGL are usually associated with viral infection of GL: in particular, Epstein Barr and human T lymphotropic virus I/II have been claimed to play a role. Neutropenia is usually less pronounced than in CD3+ LDGL patients. Clonality has rarely been demonstrated; however, when present, it correlates with an aggressive clinical course. Spontaneous regression of lymphocytosis has been reported in both CD3+ and CD3- patients. CONCLUSIONS Lymphoproliferative disease of granular lymphocytes is a well recognized disorder which encompasses a large spectrum of conditions, ranging from mild asymptomatic lymphocytosis to aggressive, usually fatal, disorders. Diagnosis of this disease is related to the demonstration that a discrete subset of GL is chronically expanded. Therapy should be delayed in asymptomatic patients; however, when needed, the combination of methotrexate or cytoxan and steroids represents the best approach.