Prostate cancer has a variable clinical outcome and, therefore, there is a clear need for novel molecular markers that are specifically associated with biologically aggressive disease to improve staging and prognostication and also to provide mechanistic information to facilitate treatment selection. Different candidate biomarkers have been identified that are linked to patient prognosis and/or response to specific treatments. Such molecules are involved in diverse cellular processes (including cell cycle regulation, cell death and apoptosis, signal transduction, cell adhesion, and angiogenesis) within which aberrant activity of several regulatory pathways has been seen in prostate cancer. Although the number of molecular markers continues to grow, mainly because of the advent of high-throughput methods, more work needs to be done to develop uniform standards for their characterization to enable comparison of markers across studies. Moreover, a rate-limiting step in the development of molecular markers is large-scale clinical assessment and their evaluation in the context of prediction model improvement. In fact, thus far, only a few studies have tested and demonstrated whether the addition of new biological markers improves the accuracy of standard clinical models (nomograms) in predicting biochemical progression in patients with clinically localized prostate cancer who underwent radical prostatectomy. Cancer 2009;115(13 suppl):3058–67. © 2009 American Cancer Society.