The therapy of non-small cell lung cancer (NSCLC) has reached a plateau in improving patient survival, with overall disappointing results. Thus, clinical research for new treatment strategies is warranted. Advances in the singling out molecular targets for NSCLC treatment has granted the development of several new biological agents. In the present paper we describe the main clinical data currently available on targeted agents in the treatment of NSCLC, focusing on epidermal growth factor receptor family inhibitors, angiogenesis inhibitors, signal transduction inhibitors, eicosanoid pathway inhibitors, vaccines and gene therapy. Several targeted agents have been introduced into clinical trials in NSCLC, mainly in advanced disease, with the first phase III study results being recently made available. To date, few of these new agents can offer hope of a substantial impact on the natural history of NSCLC, and negative results are more commonly reported than positive ones. Nevertheless, clinically-meaningful advances have already been achieved in chemotherapy refractory advanced NSCLC patients, with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, representing a further chance of tumor control and symptom palliation. Moreover, important lessons can be learned from this first generation of clinical trials.