In 2004 remarkable clinical responses in non-small-cell lung cancer (NSCLC) patients treated with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib were reported to correlate with the presence of certain somatic EGFR kinase domain mutations in tumors. Since then, a surge of enthusiasm has been encountered in the field of molecular and clinical oncology. Beyond the promise of a tailored medicine, questions about the molecular mechanisms underlying the observed effects have arisen. In vitro analysis of NSCLC cells with endogenous EGFR mutations, recombinant expression of EGFR variants by transfection of several cell lines and the generation of transgenic mice expressing mutant EGFR were applied to study the impact of these genetic alterations on cellular signaling and cell fate. This review outlines the current mechanistic knowledge derived from such studies and discusses the relevance of EGFR kinase domain mutations for EGFR-directed therapies, including monoclonal antibodies.