The promise of individualized treatment is gradually being fulfilled, and targeted therapy is becoming a powerful strategy to treat selected patients based on their molecular profile. For metastatic colorectal cancer (mCRC) patients anti-EGFR (epidermal growth factor receptor) targeted therapy has markedly improved disease control and survival. However, only a subgroup of patients with mCRC respond to anti-EGFR treatment, and selecting the patients with a positive effect from treatment is important for both the patient and the society. Patients with mutations in the KRAS gene are known as non-responders to anti-EGFR treatment and, consequently, KRAS testing has been employed in routine clinical practice for patient selection. However, a large number of the KRAS wildtype patients do not respond to this treatment. The molecular mechanism underlying response is not fully understood, and other members of the KRAS-BRAF pathway and PI3K-AKT pathway are investigated as predictive biomarkers. Furthermore, concordance of mutation status of primary tumors and their corresponding hepatic or pulmonary metastases, as well as treatment-induced mutations, possess another challenge for properly tailoring the appropriate therapy to this patient group. In this review, molecular biomarkers involved in prediction of response to anti-EGFR treatment are discussed.