The EGF receptor (EGFR) is important in the regulation of proliferation, apoptosis and angiogenesis in cancer. EGFR inhibitors have become a mainstay of treatment of metastatic colorectal cancer, in particular KRAS wild-type patients in 50–60% of patients. Despite this many patients do not respond to these agents. Over the last few years the molecular basis of resistance to EGFR inhibitors has been elucidated to a certain degree. Mutations in KRAS and the NRAS exon are unlikely to respond to EGFR inhibitors. Other mutations, such as BRAF, PI3KCA/AKT and MET, may also lead to resistance. A greater understanding of the molecular basis for resistance may lead to ways of overcoming this, leading to improvements in care for patients.