Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL.