The treatment of metastatic colorectal cancer (nCRC) underwent a clear evolution between the 1990’s and mid 2000’s, largely through the introduction of new cytotoxic agents and combinations of these with agents targeting angiogenic pathways and the epidermal growth factor receptor (EGFR). However, arguably, this progress has slowed over the last decade relative to common cancers such and lung cancer. One approach in advancing our treatments will likely come from a better molecular stratification of CRC into biologically driven subtypes. Perhaps the “lowest hanging fruit” is with the BRAF oncogene. Mutations in BRAF are found in approximately 10% of patients with metastatic colorectal cancer (mCRC). Classically, these mutations are common in the sessile serrated adenoma pathway of adenoma to carcinoma progression, and are associated with unique molecular features, including microsatellite instability, hypermethylation, and minimal chromosomal instability. It is now well recognized that mutations in BRAF play a clear pathogenic role, particularly in patients with metastatic disease who have the worst prognosis of any of the molecularly defined patient subgroups. There is therefore both a critical need and clear opportunity for the development of agents that effectively target this pathway in mCRC. However, initial attempts to target BRAF selectively with BRAF inhibitors alone were disappointing, with little meaningful single agent activity seen with agents that were very successful in BRAF mutant melanoma. A number of preclinical studies have identified almost immediate resistance developing via other pathways, in particular through EGFR. Based on this, multiple groups including ours are undertaking clinical trials to test these hypotheses, with encouraging early results. In addition to this, further insights into BRAF biology in the clinical setting are being made, enabling further rational approaches to treating these cancers. An overview of where targeting BRAF mutant CRC is at, including local initiatives/trials will be presented, in the context of how we are approaching treating rare CRC subsets.