Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are always strongly CD20 + and CD22 + , and also CD25 + unless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47-61% complete remissions (CRs), several of them ongoing after 9-10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL.