Cetuximab and panitumumab are monoclonal antibodies used in the treatment of metastatic colorectal cancer (mCRC) by selectively targeting the epidermal growth factor receptor (EGFR) axis. Studies have shown that mutations in codons 12/13 of exon 2 of the KRAS gene render these therapies ineffective. As a result, the National Comprehensive Cancer Network and American Society of Clinical Oncology recommend KRAS mutation testing in mCRC. Appropriate testing depends on the coordinated efforts of the entire treatment team, including the pathologist, who selects the tumor sample and testing platform as well as interprets and reports results. In addition to describing rationale and methodologies for KRAS mutation testing, the authors also summarize their algorithmic approach and elaborate the potential role of newer molecular biomarkers to predict anti-EGFR resistance in wild-type KRAS tumors.