Pancreatic cancer is a deadly disease with an annual incidence rate nearly equal to its mortality rate. Incremental improvement in outcome has been seen in the last 25 years, illustrating the critical need for novel approaches and intensive research investment. Expression profiling of pancreatic cancers has led to an explosion of informative gene-expression changes and the identification of new diagnostic and prognostic markers. However, the search for genes that are of functional significance in these large datasets continues to be much more challenging. One approach to focusing on genes or pathways that are likely to be more biologically relevant is to study those that are of prognostic significance. This review will therefore focus on the advantages of a prognostic gene signature for pancreatic cancer, the advances that have been made thus far, the approaches used and the challenges that remain.