Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced-stage non-small-cell lung cancer (NSCLC). One potential explanation for this lack of benefit is a negative interaction or antagonism between chemotherapy and EGFR TKIs when delivered concomitantly. Support for this line of reasoning is provided by preclinical data demonstrating that EGFR TKIs induce primarily a cytostatic effect resulting from a G1 cell cycle arrest in cell lines with wild-type EGFR, reducing cell cycle phase-dependent activity of chemotherapy, whereas they induce apoptotic cell death in tumors with EGFR-activating mutations. Because the great majority of NSCLC tumors consist of wild-type EGFR, sequence-specific interactions of EGFR TKI/chemotherapy combinations might negatively influence the efficacy of these regimens in patients with NSCLC. Further evidence is provided by EGFR mutational analysis in patient tumor specimens from the TRIBUTE study. Herein we provide the preclinical and clinical rationale for studies examining the concept of pharmacodynamic separation as a means for overcoming hypothesized antagonism of EGFR TKIs and chemotherapy.