Hyman, Diamond, and colleagues carried out a prospective, blinded study to quantitatively detect the BRAF^V600E mutation in circulating tumor cell-free DNA (cfDNA) from the urine and plasma of patients with Langerhans cell histiocytosis or Erdheim-Chester disease. Urinary cfDNA analysis defined the BRAF genotype of all 30 patients and was 100% concordant with tissue genotypes among treatment-naïve patients. Furthermore, serial urinary cfDNA analyses in patients treated with a BRAF inhibitor or immunomodulatory therapy showed a progressive decrease in BRAF^V600E allele burden, consistent with radiographic evidence of disease improvement. Tissue and cfDNA genotyping also identified a previously unreported somatic KRAS^G12S mutation in a BRAF wild-type patient. These data suggest cfDNA testing as a reliable, noninvasive method to detect BRAF^V600E mutations and monitor response to therapy in histiocytic disorders. For details, please see the article by Hyman, Diamond, and colleagues on page 64.