Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström's macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin's lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin's lymphoma.