Treatment of BRAF-mutant colorectal cancer (CRC) traditionally represents an unmet need, mainly due to its unfavourable prognostic outlook, limited options for targeted treatment and scarce benefit from epithelial growth-factor receptor (EGFR) inhibitors. Recently, the development of BRAF V600E inhibitors has expanded the therapeutic armamentarium, although exclusive targeting of BRAF has proved to be an unsuccessful strategy due to reactivation of the mitogen-activated protein kinase pathway through multiple escape mechanisms. Combination strategies that exploit simultaneous inhibition of BRAF, EGFR and/or mitogen-activated protein/extracellular signal-regulated kinase have achieved greater success, with the BEACON CRC trial providing the first evidence for an improvement in survival with a chemotherapy-free approach in pre-treated patients with CRC, leading to regulatory approval for the combination of encorafenib and cetuximab. Subsequent research efforts attempt to build on these foundations, exploring targeted maintenance strategies and conceivably moving the combination towards the first line of therapy soon, as well as laying the foundation for the use of liquid biopsy as a guidance tool in a precision oncology approach.