Background: Recent clinical trials suggest that epidermal growth factor receptor (EGFR)-targeted agents could benefit many patients with cancer. Methods: We review the current status of several EGFR-targeted therapies in cancer patients and address the efficacy of theses drugs as monotherapy or in combination with other drugs and/or treatments. Results: Cetuximab is the most widely studied anti-EGFR monoclonal antibody. Other monoclonal antibody agents under investigation are panitumumab, matuzumab, MDX-447, nimutozumab, and mAb806. Extensive research has also evaluated the efficacy of EGFR tyrosine kinase inhibitors such as erlotinib, gefitinib, EKB-569, lapatinib (GW572016), PKI-166, and canertinib (CI-1033). All of these agents have been studied for the treatment of colorectal, lung, breast, pancreatic, renal, head and neck, gynecologic, and prostate cancer. Currently, cetuximab and panitumumab are FDA approved for the treatment of metastatic colorectal cancer. Additionally, cetuximab is approved for head and neck cancer. Erlotinib is FDA approved for advanced/metastatic lung cancer. Erlotinib in combination with gemcitabine is approved for advanced/metastatic pancreatic cancer treatment. Conclusions: EGFR-targeted agents have already shown utility in different scenarios. Researchers are continuously investigating additional cancer types and combined treatment modalities that could also benefit from the use of EGFR-targeted agents. Careful patient selection through the identification of specific biologic markers, such as gene expression, genomic polymorphism, and posttranslational modifications of EGFR downstream effectors, most likely will contribute to the successful use of these agents.