The advent of the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs), cetuximab and panitumumab has expanded the range of treatment options for metastatic colorectal cancer (CRC). Despite these agents have paved the way to individualized therapy, our understanding why some patients respond to treatment whereas others do not remain poor. The realization that detection of positive EGFR expression by IHC does not reliably predict clinical outcome of EGFR-targeted treatment has led to an intense search for alternative predictive biomarkers. Data derived from multiple phase III trials have indicated that KRAS mutations can be considered a highly specific negative biomarker of benefit to anti-EGFR mAbs. Oncologists are now facing emerging issues in the treatment of metastatic CRC, including the identification of additional genetic determinants of primary resistance to EGFR-targeted therapy for further improving selection of patients, the explanation of rare cases of patients carrying KRAS-mutated tumours who have been reported to respond to cetuximab and panitumumab and the discovery of mechanisms of secondary resistance to EGFR-targeted therapy. Current data suggest that, together with KRAS mutations, the evaluation of EGFR gene copy number (GCN), BRAF, NRAS, PIK3CA mutations or loss of PTEN expression could also be useful for selecting patients with reduced chance to benefit from anti-EGFR mAbs. This review aims to provide an updated of the most recent data on predictive and prognostic biomarkers within the EGFR pathway, the challenges this emerging field presents and the future role of these molecular markers in CRC treatment.