Progress in the treatment of patients with hairy cell leukemia (HCL) has led to a significant change in the natural history of the disease. With current regimens, the majority of patients achieve a complete remission, and their survival curves are similar to those for appropriate age-matched individuals without the disease. At the same time, new technologies are allowing better understanding of the molecular mechanisms responsible for the pathogenesis of this and other indolent lymphoid neoplasms. Several studies using modern techniques with different sensitivities have demonstrated the persistence of minimal residual disease (MRD) after therapy with nucleoside analogues in majority of patients. However, it is not clear whether such MRD would invariably lead to leukemia recurrence or what level of MRD can predict relapse. The role of monoclonal antibodies, naked or conjugated with toxins, in the management of HCL and their ability to eradicate MRD is under investigation. Whether such strategies of chemoimmunotherapy would lead to further improvements in the outcome of patients with HCL needs to be further investigated.