Our understanding of the genetic and nongenetic molecular alterations associated with anti-epidermal growth factor receptor (EGFR) therapy resistance in colorectal cancer (CRC) has markedly expanded in recent years. Mutations in RAS genes (KRAS/NRAS exons 2, 3, or 4) predict a lack of clinical benefit when anti-EGFR monoclonal antibodies (mAbs) are added to chemotherapy. Genetic events in additional nodes of the mitogen-activated protein kinase (MAPK)-phosphoinositide 3-kinase (PI3K) pathways that bypass EGFR signaling, such as BRAF or PIK3CA mutations or KRAS, ERBB2, or MET amplifications, also may confer resistance to cetuximab or panitumumab. Polymorphisms that block antibody binding as a result of EGFR extracellular domain mutations have been reported. Nongenetic mechanisms, including compensatory activation of receptor tyrosine kinases HER3 and MET, together with high expression of the ligands amphiregulin, transforming growth factor alpha heregulin, and hepatocyte growth factor in the tumor microenvironment also are thought to be involved in resistance. In one-third of the samples, more than one genetic event can be found, and nongenetic events most likely coexist with gene alterations. Furthermore, activation of a gene expression signature of epithelial-mesenchymal transition has been associated with reduced cellular dependence on EGFR signaling. Collectively, this body of work provides convincing evidence that the molecular heterogeneity of CRC plays an important role in the context of resistance to anti-EGFR therapy. Herein, we discuss how this knowledge has been translated into drug development strategies to overcome primary and acquired anti-EGFR resistance, with rational combinations of targeted agents in genomically selected populations, second-generation EGFR inhibitors, and other agents expected to boost the immune response at the tumor site.