Langerhans cell histiocytosis (LCH) is a disorder of myeloid neoplasia of dendritic cells that affects 1 in 200,000 children <15 years of age and even fewer adults. LCH presents with a spectrum of clinical manifestations. High-risk stratification is reserved for infiltration of blood, spleen, liver, and lungs. After decades of debate on the disease pathogenesis, a neoplastic mechanism is now favored on the basis of LCH cell clonality, rare cases of familial clustering, and recent evidence of mutations involving the Ras/Raf/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase) pathway in lesional biopsy specimens. Somatic mutations are most often found in BRAF (BRAF^V600E in 47.1% of reported patients) and MAP2K1 (21.7%) and uncommonly found in MAP3K1 or ARAF. Increased levels of phospho-ERK in lesional tissue, activation of Ras/Raf/MEK/ERK signaling with these mutations in vitro, and the mutual exclusivity of these mutations in a given patient suggest a central role for activation of the Ras/Raf/MEK/ERK oncogenic pathway in LCH. Immunohistochemical assessment of lesional tissue using the VE1 BRAF^V600E mutation–specific antibody can serve as a screening tool for BRAF^V600E-positive LCH. Case reports suggest that BRAF^V600E-positive LCH unresponsive to standard therapy might respond to B-Raf-MEK pathway inhibition, but rigorous randomized clinical trials have yet to be performed.