The epidermal growth factor receptor (EGFR) is recognized as an important player in colorectal cancer (CRC) initiation and progression. This membrane-bound receptor tyrosine kinase (RTK) has therefore become a key target of therapeutic strategies designed to treat metastatic CRC, in particular with monoclonal antibodies (mAbs) against the extracellular domain of the receptor. KRAS is an effector molecule responsible for signal transduction from ligand-bound EGFR to the nucleus. Activating mutations in KRAS are recognized as a strong predictor of resistance to EGFR-targeted mAbs. Routine testing of all patients with CRC for KRAS mutations is now recommended; only those harboring wild-type (WT) KRAS should be candidates for such therapies, thus improving outcomes, and minimizing unnecessary toxicity and cost. Even though the identification of the importance of KRAS status has marked a turning point in the treatment of metastatic CRC (mCRC), it is becoming apparent that other critical elements in the complex signaling pathways related to EGFR may also contribute vital information that will aid in treatment decisions and ultimately benefit patients.