The crucial role of EGFR signaling in the survival of several tumors, including CRC, is supported by the approval of anti-EGFR targeted therapies; unfortunately, resistance to target therapy inevitably emerges; HER2 has recently been shown to represent one potential resistance mechanism leading to anti-EGFR antibody therapy resistance in KRAS wild type tumors [66]. This evidence concerns the gene ERBB2 and colorectal carcinoma.