The epidermal growth factor receptor (EGFR) pathway is an important target in the treatment of advanced non-small-cell lung cancer. Therapeutic modulation of this pathway has focused on inhibiting the EGFR tyrosine kinase or competitively binding the receptor. Each method of EGFR inhibition is imperfect, with alternate cellular mechanisms variably enabling continued proliferation and malignant growth. In addition, de novo or acquired resistance is common with either one of these approaches. The use of both strategies simultaneously to block the EGFR signaling cascade, so-called dual inhibition, might theoretically overcome these limitations and improve efficacy. Preclinical data support this concept, and clinical trials are under way to investigate the safety and efficacy of combined EGFR inhibition.