Hairy cell leukemia (HCL) is an indolent B-cell malignancy, with long-term responses to purine analogs, but with decreasing efficacy and increasing toxicity with repeated courses. Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCLv, lacking CD25, Anxa1, TRAP, and BRAF V600E, is more aggressive and less purine analog-sensitive. A molecularly defined IGHV4-34+ variant is also resistant whether HCL or HCLv immunophenotypically. Traces of HCL cells, termed minimal residual disease (MRD), accompany most with complete remission (CR) and may cause relapse. Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton's tyrosine kinase.