Classic hairy cell leukemia (HCL) is a rare mature B-cell malignancy associated with pancytopenia and infectious complications due to progressive infiltration of the bone marrow and spleen. Despite tremendous therapeutic advances achieved with the implementation of purine analogues such as cladribine into clinical practice, the culprit biologic alterations driving this fascinating hematologic disease have long stayed concealed. Nearly 10 years ago, BRAF V600E was finally identified as a key activating mutation detectable in almost all HCL patients and throughout the entire course of the disease. However, additional oncogenic biologic features seem mandatory to enable HCL transformation, an open issue still under active investigation. This review summarizes the current understanding of key pathogenic mechanisms implicated in HCL and discusses major hurdles to overcome in the context of other BRAF-mutated malignancies.