Background: Histiocytic neoplasms (HN) are clonal hematopoietic disorders characterized by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway. BRAF inhibition is highly effective for patients with HN harboring the BRAFV600E mutation, and implementation of BRAF inhibitors transformed management of BRAFV600E-mutated Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH). No standard or approved therapies existed, however, for patients with HN lacking the BRAFV600E mutation. Efficacy of mitogen-activated protein kinase (MEK) inhibition for HN harboring various MAPK pathway mutations has been observed in case reports and series. We present here results from 26 patients treated in a phase 2 trial of single-agent cobimetinib for adults with HN (NCT02649972). The data were submitted to the Food and Drug Administration (FDA) in a supplemental new drug application for cobimetinib, and FDA approval was granted in October, 2022.