Panitumumab is a fully human, monoclonal antibody targeting the EGF receptor with proven clinical activity in KRAS wild-type metastatic colorectal carcinoma. Treatment with panitumumab has been shown to significantly improve response rate and progression-free survival in this subgroup of patients, with a manageable toxicity profile. Panitumumab’s first worldwide indication was as a single agent in chemorefractory patients. Recently, the EMA approved its use as part of a chemotherapy regimen in first- and second-line settings, following the encouraging results of large randomized Phase III trials. In order to identify patients with higher chances of benefiting from the treatment, additional molecular aberrations in the EGF receptor signaling pathway are being investigated as predictive biomarkers. In this article we review 10 years of drug development, focusing on the clinical evidence for panitumumab’s indication in metastatic colorectal cancer and future strategies of investigation.