In this issue of Blood, Nelson et al describe a novel somatic ARAF mutation in a child with Langerhans cell histiocytosis (LCH) and demonstrate that the encoded protein has strong gain-of-function properties. Importantly, this mutant A-Raf molecule is sensitive to inhibition by vemurafenib, a potent and selective Raf kinase inhibitor that is Food and Drug Administration (FDA)-approved for the treatment of advanced melanoma. This work thus identifies a new driver mutation in LCH that is potentially actionable in the clinic.