Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been shown to produce dramatic and durable responses in a fraction of non-small cell lung cancer patients. During recent years, clinical and biological predictors for TKI sensitivity have been identified. Among clinical features, never-smoking history seemed the most critical factor, probably because of the different spectrum of molecular abnormalities associated with cigarette smoking exposure. Among biological predictors, several studies indicate that EGFR mutations and increased EGFR gene copy number are implicated in response to TKI therapy, with conflicting results in survival. Mutations in the EGFR gene, as well as in K-ras and HER2 genes, seemed to impair TKI effects, leading to TKI resistance. Because the vast majority of available data come from retrospective studies there is an urgent need to validate these results in prospective trials. Several studies have recently been completed and these data could indicate the way for a proper selection of patient candidate for TKI therapy.