KRAS mutations in colorectal and lung cancers predict failure to respond to therapies that target the EGFR. Significant percentages of patients with KRAS wild-type tumors also fail to respond to these therapies. Relapse occurs in patients with KRAS wild-type and mutant tumors, with moderately longer progression-free survival in patients with KRAS wild-type tumors. Colon and lung tumors frequently carry KRAS mutant tumor subpopulations not detected by DNA sequencing. This suggests detected and undetected KRAS mutant subpopulations in colon and lung tumors are undermining the efficacy of anti-EGFR therapies. Therefore, consideration should be given to combining therapies that target KRAS mutant cells with those that downregulate EGFR signaling. As tumors are frequently polyclonal in origin and comprised of distinct clonal populations carrying complementing genetic and/or epigenetic lesions, preclinical models that assess the efficacy of combination therapies in the context of heterogeneous tumor cell populations will be essential for progress in this area.