This study characterized a panel of NSCLC cell lines as well as a stably transfected cell model expressing wild-type and mutated EGFR variants in terms of response to the EGFR-targeting drugs, gefitinib and cetuximab. The examinations support the notion that response to gefitinib is neither exclusive nor strictly determined by the presence of EGFR kinase mutations. Yet, cells expressing EGFR kinase domain mutations tended to generally respond better to treatments with gefitinib compared to those with wild-type EGFR. On the other hand, preliminary studies suggesting that cellular sensitivity to cetuximab is determined by factors other than EGFR kinase domain mutations could be substantiated through a robust set of data. Moreover, several promising candidate genes differentially expressed in gefitinib sensitive and resistant NSCLC cell lines were revealed by a global mRNA expression analyses. In addition, though statistically questionable, several biologically interesting genes that are possibly involved in determining in vitro response of NSCLC cells to cetuximab have been postulated. In this work, four cancer cell models, which are long-term exposed to gefitinib or cetuximab were established and characterized in terms of gain-of-resistance towards EGFR-targeting compounds, as well as in regard to biological and molecular alterations caused by long-term treatments. It was found that gefitinib long-term treatment of primary sensitive A431 cells confered growth-resistance to this TKI, but not to cetuximab. This observation may have clinical implications for patients that relapsed on gefitinib as it suggests that they might still profit from cetuximab therapy. On the other hand long-term exposure of A431 cells to cetuximab did not render cells resistant to neither the antibody nor gefitinib in regard to in vitro growth-inhibition. Furthermore, it appeared that long-term gefitinib-treated A431 cells downregulate overall EGFR levels, while long-term cetuximab exposed cells displayed decreased EGFR surface levels but constant overall expression. In addition, a candidate-based approach identified genes that are differentially expressed in cancer cells with primary or secondary resistance to gefitinib or cetuximab. Finally, this study for the first time provided evidence that cetuximab may block metastasis-facilitating epithelial-mesenchymal-transition (EMT) in an epithelial cell line. Moreover, it was suggested that activation of the HGFR may compensate for cetuximab-mediated blockage of EGFR. This was also reflected by an increased response of this population towards treatment with HGFR inhibitors.