Here, we report a case of primary BRAF-V600E-mutant, microsatellite-stable (MSS), metastatic CRC in a 16-year-old female patient who was treated with alternating chemotherapy and EGFR-/BRAF-/MEK-targeted therapy on the basis of evidence of tumor evolution monitored by serial cell-free plasma DNA (cfDNA) sequencing assays. The gene discussed is BRAF; the disease is colorectal carcinoma.