In patients with metastatic colorectal cancer, overall survival has improved over the last decade mainly due to the use of effective targeted therapies such as anti-EGFR. However, survival improvement is linked to proper selection of patients expected to benefit from these treatments. KRAS codons 12 and 13 mutation status was the first validated molecular biomarker for anti-EGFR antibodies. Today, rare KRAS alterations and NRAS mutations were implemented, defining the ‘RAS’ status as the new validated marker of response to anti-EGFR antibodies. Moreover, other biomarkers are under investigation to screen for other targets and help with patients selection. Here, we reviewed these promising biomarkers: mutations in the RAS–MAPK and PI3K–AKT pathways genes, MET activation, HER/ErbB receptors activation (EGFR, HER2 and HER3), EGFR ligands, antibody-dependent cell-mediated cytotoxicity) and miRNAs. Further data are needed to define their impact for the treatment of patients with metastatic colorectal cancer.