Survival rates for early stage non-small cell lung cancer (NSCLC) remain unacceptably low compared to other common solid tumors. This mortality reflects a weakness in conventional staging, as 30-45% even of stage I patients harbor undetected metastasis. The need for better discrimination of high-risk patients in both stages I and II NSCLC is underscored by the documentation that adjuvant chemotherapy offers the possibility of cure for occult metastasis of NSCLC. Despite this possibility to improve survival through early intervention, however, many stage II and nearly all stage I patients with occult metastasis still forgo adjuvant chemotherapy because there has been no well-validated means of identifying those patients at highest risk. Gene expression profiles have become the gold standard for delineating risk and improving clinical decisions in early stage breast cancer. Previous efforts to develop a similarly practical and effective means of improving decision-making in the management of early stage NSCLC, however, have lacked both a clinically relevant approach and adequate large-scale validation. A PCR-based, 14-gene expression assay that uses paraffin-embedded tissue was recently reported to discriminate high- and low-risk patients with non-squamous NSCLC, and has been validated in ~1,500 patients in two large scale, international, independent, blinded studies (Lancet 2012;379:823, JAMA 2012;308:1629). The molecular profile outperforms all conventional risk criteria and staging methods at identifying patients at the highest risk of mortality after an attempt at curative surgery, even within individual staging groups. Published guidelines already recommend adjuvant chemotherapy for high-risk stage I and stage II patients; this molecular assay therefore represents a more effective means of implementing the current standard of care and of improving clinical decision-making in patients with early stage non-squamous, NSCLC.