PURPOSE OF REVIEW: Integrating targeted therapies against the epidermal growth factor receptor (EGFR) and angiogenesis pathways into standard treatment paradigms for advanced nonsmall cell lung cancer (NSCLC) have been successful, but not yet curative. Two treatment strategies, in development, seem particularly appealing for further study: insulin-like growth factor receptor (IGF-1R) and histone deacetylase (HDAC) inhibition. Several lines of evidence suggest that these novel approaches may play a relevant role in the future treatment of NSCLC. RECENT FINDINGS: Preliminary results of a phase II trial combining an anti-IGF-1R monoclonal antibody with platinum-based chemotherapy in untreated NSCLC patients have shown an encouraging response rate, particularly in those with squamous cell carcinoma, where IGFR expression is typically high. Recent data also support the clinical development of HDAC inhibitors as a strategy to counter epigenetic gene silencing and transcriptional repression of key anticancer genes. Moreover, research efforts are focusing on identifying predictive markers to appropriately select patients for maximal therapeutic benefit. SUMMARY: Here, we briefly review data regarding anti-EGFR and antiangiogenesis agents before discussing the potential roles for IGF-1R and HDAC inhibitors in NSCLC management, and the need for optimizing treatment by seeking a more personalized approach to care.