Incidental prostate cancer (PCa) has been demonstrated at autopsy in about 80% of men aged 80 years and above and also in 10%-15% of younger men aged 30-50 years in the United States. These data imply a wide variation in aggressiveness of prostate cancer, from indolent tumors to aggressive cancers that kill the patients. The use of prostate specific antigen (PSA) in screening for PCa may detect even indolent disease for which radical prostatectomy may not be necessary. Currently available criteria such as histological grade, PSA level, stage of the disease do not always predict outcome. Furthermore, only about 80% of men with metastatic PCa will respond to first line hormone manipulation and once the patient develops hormone resistant prostate cancer (HRPCa), survival remains poor. Recent genomic and proteomic studies have provided many novel molecular markers that may help to redefine prognostic parameters. This paper is a review of studies using these novel markers in order to determine whether prostate cancer patients with the following characteristics have more aggressive cancer than those without: a) high serum levels of cathepsin B, survivin, Her-2 /neu, IGFBP-2; b) low serum stefin A, IGFBP-3, c) positive immuno-staining of primary tumors for Her-2/neu, survivin and cathepsin B / stefin A ratio > 1 and d) gene expression of AMACR, HER-2/neu, high Bcl-2: Bax ratio and EZH2 in cancer cells. These markers have been chosen for review because they are among the most promising markers emerging currently.