Targeted agents directed at VEGF, such as bevacizumab, and EGFR, such as cetuximab and panitumumab, have become part of the standard treatment of metastatic colorectal cancer. Only a subset of patients seem to benefit from such treatment, and varying results have been observed when different lines of treatment are used in combination with different cytotoxic drugs. Preclinical and early clinical data have shown promising results for the combination of anti-VEGF and anti-EGFR treatment. However, two recent phase III trials, CAIRO2 and PACCE, have shown a detrimental effect of adding an anti-EGFR antibody to standard chemotherapy plus bevacizumab. We discuss issues that may explain these unexpected results.