In an effort to improve the survival of cancer patients, new therapeutic approaches focusing on the molecular mechanisms that mediate tumour cell growth or survival have gained much attention. In particular, EGF-R and VEGF/VEGF-R have been extensively investigated as targets for anti-neoplastic therapy. Agents that selectively target EGF-R, erbB-2, VEGF-R-2 or VEGF have shown promising activity in clinical trials, and several are now approved for use in selected cancer indications. However, all patients ultimately develop resistance to these drugs. Thus, there is a great need to understand how patients become resistant to effective therapies for these cancers since this approach may lead to improvements in therapies that target EGF-R and VEGF/VEGF-R. Pre-clinical studies have begun to shed light on the mechanisms of resistance to anti-angiogenetic drugs and to date four mechanisms of resistance have been identified (1) upregulation of bFGF, (2) overexpression of MMP-9, (3) increased levels of SDF-1alpha and (4) HIF-1alpha-induced recruitment of bone marrow-derived CD45+ myeloid cells. In addition, the molecular mechanisms of resistance to EGF-R modulating agents can be attributed to several general processes: (1) activation of alternative tyrosine kinase inhibitors that bypass the EGF-R pathway (e.g. c-MET and IGF-1R), (2) increased angiogenesis, (3) constitutive activation of downstream mediators (e.g. PTEN and K-ras) and (4) the existence of specific EGF-R mutations. K-ras mutations have been significantly associated with a lack of response to EGF-R tyrosine kinase inhibitors in patients with NSCLC and with a lack of response to cetuximab or to panitumumab in patients with advanced colorectal cancer. The identification of these resistance mechanisms has led to clinical trials using newly designed targeted therapies that can overcome resistance and have shown promise in laboratory studies. Ongoing research efforts will likely continue to identify additional resistance mechanisms, and these findings will hopefully translate into effective therapies for different cancers.