The results of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.21 study, a phase III, randomized, placebo-controlled trial of erlotinib in patients with advanced NSCLC who had failed first-line or second-line chemotherapy, provided new treatment options for lung cancer. Given that only a small percentage of patients may benefit from treatment with inhibitors that target the EGF receptor (EGFR), substantial effort has been devoted to identifying biomarkers that are predictive of the highest likelihood of benefit from these drugs. Several markers, including EGFR tyrosine kinase domain mutation, EGFR gene copy number and KRAS mutation, have been investigated extensively, but results obtained to date remain controversial. This feature review discusses available data and the basis for the controversies.