The rationale to inhibit the epidermal growth factor receptor (EGFR) tyrosine kinase family as an approach to cancer chemotherapy has continued to grow stronger over the last 10 years. Both preclinical and clinical data strongly support the involvement of these receptors in the formation and progression of human cancers, as well as establish a high correlation in cancer patients between receptor/ ligand expression and poor prognosis. During the past 4 years, significant progress has been made in the area of EGFR tyrosine kinase inhibitors, and new structural classes have emerged that exhibit enormous improvements with regard to potency, specificity, and in vitro and in vivo activity. Very recently, further advancements in this field have been made whereby very specific, irreversible inhibitors of the EGFR family have been synthesized that provide unique pharmacological properties and exceptional efficacy. The in vivo performance of these modern kinase inhibitors has improved to the point where several compounds are either in clinical trials or very near to that point in their development. This review will briefly address the justification for targeting the EGFR family for cancer therapeutics, and then will highlight some of the more promising kinase inhibitors that are in development.