The use of anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapies in patients with metastatic colorectal cancer is guided by the presence of activating point mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS and NRAS genes in the primary tumor. Although these mutations have been incorporated into the prescribing information for both cetuximab and panitumumab, highlighted in the National Comprehensive Cancer Network Guidelines, and routinely tested, a number of controversial issues and unanswered questions related to these mutations and their clinical significance remain. In the present review, we explored the contradictory data related to the prognostic value of KRAS mutations, the reported frequent discordance of KRAS mutations, and the reported nonequivalence of some of these mutations. We also considered the issues related to incorporating additional mutations into the already accredited and approved assays and the challenges created by changing an assay's analytical and clinical limits of detection. We also discuss the lack of biologic data supporting the pathogenicity of newly described clinically actionable mutations and explore the uncertainty regarding the clinical significance of low-frequency mutations, highlighting the importance of correcting allele frequencies for tumor purity. We also considered the importance of distinguishing the significance of low-frequency RAS mutations in tumors previously not treated or treated with anti-EGFR therapies and explore new technologies capable of detecting emerging polyclonal RAS mutations that appear to confer drug resistance.