The detection and treatment of prostate cancer was dramatically altered with the advent of the prostate-specific antigen (PSA), and its usefulness particularly in following patients after radical prostatectomy is unquestioned. The ability of PSA to predict prostate cancer, and in particular clinically relevant prostate cancer, has come into doubt in recent years and has led to the search for better diagnostic markers for prostate cancer. Both serum and urine biomarkers are in various stages of development, and many of these have been discovered through progress in genomic and proteomic analysis. Some of these perform better in limited study than our current standards of diagnosis (ie, PSA and digital rectal examinations), and some have suggested the capacity to predict stage and likelihood of recurrence. Further study is needed to validate many of these markers, and the future of prostate cancer detection will likely lie in multiplex assays that test a number of markers concomitantly to assess prostate cancer risk.