Activation of the epidermal growth factor receptor (EGFR)-dependent intracellular signaling pathway has a relevant role in the development and the progression of several human cancers. However, EGFR-targeted therapies have a significant clinical activity only in a subgroup of cancer patients whose tumors express the EGFR. This is due in part to the activation of several other signal transduction pathways which will be EGFR-independent and could be responsible for cancer cell growth. A clinically relevant field of research is the development of rational, biologically based multi-targeted therapy combinations which will block cancer cell escape from single target inhibition, such as the use of EGFR inhibitors in monotherapy. A number of clinical trials with EGFR inhibitors in combination with classic cytotoxic agents have been undertaken with both interesting and disappointing results. It is, therefore, felt that combinations of EGFR inhibitors and other novel agents, which is based on the mechanistic knowledge of complementary signaling pathways whose concerted inhibition would efficiently block cancer cell growth, is the rationale therapeutic approach. Some of these pathways [i.e., mammalian target of rapamycin (mTOR), vascular endothelial growth factor receptor (VEGFR), ras/mitogen-activated protein kinase (MAPK) signaling, or insulin like growth factor receptor (IGFR)] which are functionally related to the activity of the EGFR will be discussed in this review to provide a scientific rationale for the combination of drugs which target these pathways with anti-EGFR agents.