The evolution of our understanding of the molecular biology of colorectal cancer has revolutionized our treatment paradigm. As we move into an era of genomic sequencing and tumor molecular profiling that will one day provide integral information on prognostic and predictive biomarkers, we are better able to personalize therapy accordingly, improving patient outcomes and minimizing unnecessary toxicity and cost. Progress has been made in identifying biomarkers that confer poorer outcomes with targeted therapy. KRAS exon 2 mutations have been established to be negative predictive biomarkers to anti-EGFR therapies, but more recent data support extended RAS testing that has recently been integrated into clinical practice. In this article, we review the evolution of KRAS and extended RAS testing as negative predictive biomarkers to anti-EGFR therapy, both as monotherapy and in combination with chemotherapy in advanced colorectal cancer.