Novel therapeutic approaches targeting signaling pathways involved in cell proliferation, apoptosis, angiogenesis and metastasis have been under clinical development. Of many potential targets in adult solid tumors, the epidermal growth factor receptor (EGFR) has been the most extensively studied since its over-expression has been observed in several common solid tumors. However, the insurgence for resistance to drugs targeting the EGF-receptor has been described. The understanding of the mechanisms which are responsible of resistance to EGFR inhibitors could lead to the development of improved strategies to integrate anti-EGFR therapies. In this review, we will describe the latest new strategies developed to optimize the therapeutic effects of EGFR inhibitors, by exploring combinations with other molecular targeted approaches including other erbB family member inhibitors, drugs with different structure and mechanism of action, other tumor cell-directed signal transduction inhibitors, anti-angiogenic treatment modalities, and the use of broad spectrum EGFR tyrosine kinase inhibitors.