In the past few years, knowledge on the resistance to therapy with monoclonal antibodies in colorectal cancer has evidenced the role of mutations in a series of proteins involved in the epidermal growth factor receptor (EGFR) pathway. KRAS mutations can influence the response to therapy, as demonstrated by clinical utilization of cetuximab and panitumumab that are indicated only in KRAS wild-type colorectal cancer. Recently, it has been demonstrated that the mutational status of other proteins like NRAS, BRAF, PI3K or alterations in EGFR and other tyrosine kinase receptors are involved both in primary and secondary resistance to anti-EGFR monoclonal antibodies and could predict the patient response and survival. Many therapeutic strategies have been studied to overcome resistance to these drugs, which include the use of drugs directed against proteins involved in the intracellular signalling pathway of EGFR, such as inhibitors of MEK, BRAF, PI3K/mTOR, or directed against other tyrosine kinase receptors such as MET and HER2. This review will analyse recent strategies utilized to overcome resistance to anti-EGFR monoclonal antibodies in colorectal cancer.