This chapter presents a state of the art summary of hairy cell leukemia (HCL) to its definition, biology, epidemiology, disease mechanisms, clinical signs, diagnosis, treatment and prognosis. HCL is a mature B-cell lymphoproliferative disorder included as a distinct entity in the World Health Organization classification of hemopoietic and lymphoid tumors. A major advance in the understanding the molecular pathogenesis of HCL was the discovery of a mutation on the BRAFV600E gene as detected by whole exome sequencing in virtually all patients with HCL. The blood counts show variable degrees of anemia, thrombocytopenia, and neutropenia. Macrocytosis is frequent, and monocytopenia is characteristic in active HCL. The differential diagnosis arises with other primary splenomegalic disorders such as splenic marginal zone lymphoma, unclassifiable splenic B-cell leukemias/lymphomas, HCL-variant, and—rarely—with primary myelofibrosis and aplastic anemia. Since the introduction of effective treatments three decades ago, the prognosis for HCL is good overall.