Treatment of colorectal cancer (CRC) with conventional anticancer treatments has clear benefits in both adjuvant and metastatic settings; however, there are undeniable limitations both in terms of efficacy and toxicity. Molecular targeted therapies have emerged as a new generation of molecules aiming to increase anticancer activity while minimizing side effects. A further desirable attribute is the capacity to be combined with chemotherapy or radiotherapy. Epidermal growth factor receptor inhibitors have emerged to impact outcomes of cancer patients and gain routine clinical use. Cetuximab and panitumumab are the 2 most advanced such compounds. Both have achieved regulatory approval for metastatic CRC. This topic review will focus on the molecular basis and the mechanisms of action of epidermal growth factor receptor inhibitors, the clinical trials in this field and future trends of such compounds in CRC.