Both the multi-targeted antifolate pemetrexed and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib have established roles in the treatment of advanced non-small cell lung cancer (NSCLC). Given different mechanisms of action and minimal overlapping toxicities, combinations of these agents have been considered. However, four previous phase III trials investigating concurrent chemotherapy with or without EGFR TKIs showed no clinical benefit. Based on preclinical data, we developed a model of pharmacodynamic separation to avoid potential negative interactions between chemotherapy and EGFR TKIs in tumors containing wild-type EGFR. This review summarizes the background, scientific rationale and early clinical data in support of intercalation of intermittent erlotinib dosing with pemetrexed as a means of achieving pharmacodynamic separation. Ongoing research efforts investigating this concept are reviewed.