Most cancer treatments benefit only a minority of patients. This has led to a widespread interest in the identification of gene-expression-based prognostic signatures. Well-developed and validated genomic signatures can lead to personalized treatment decisions resulting in improved patient management. However, the pace of acceptance of these signatures in clinical practice has been slow. This is because many of the signatures have been developed without clear focus on the intended clinical use, and proper independent validation studies establishing their medical utility have rarely been performed. The practicing physician and the patient are thus left in doubt about the reliability and medical utility of the signatures. We aim to provide guidance to physicians in critically evaluating published studies on prognostic gene-expression signatures so that they are better equipped to decide which signatures, if any, have sufficient merit for use, in conjunction with other factors in helping their patients to make good treatment decisions. A discussion of the lessons to be learned from the successful development of the Oncotype DX genetic test for breast cancer is presented and contrasted with a review of the current status of prognostic gene-expression signatures in non-small-cell lung cancer.