In prostate biopsies and in prostatectomy specimens, the Gleason score remains the strongest prognosticator of prostate cancer progression, in addition to serum PSA level and DRE findings, in spite of numerous potential biomarkers discovered during the last few decades. Inter- and intratumoural heterogeneity may have limited the employment of tissue biomarkers on prostate biopsies. Nevertheless, the monoclonality of morphologically heterogeneous (Gleason score 7) tumour foci would suggest that genetic biomarkers, arising early in prostate carcinogenesis, may overcome issues related to intratumoural heterogeneity. In spite of the above limitations, a few biomarkers including the proliferation marker Ki-67 and genetic markers such as c-MYC and PTEN have consistently shown their independent prognostic impact both for biochemical recurrence and for clinical outcome parameters such as metastatic disease or prostate-specific mortality. The routine application of biomarkers requiring immunostaining (e.g. Ki-67) has particularly been hindered by the lack of standardized protocols for processing and scoring, while the application of fluorescence in situ hybridization (FISH) technology is considered more labour intensive but better standardized. Future steps to enhance the uptake of prostate tissue biomarkers should be focused on prospective studies, particularly on prostate biopsy specimens, using protocols that are highly standardized for the processing and scoring of the biomarkers. A few recently developed RNA-based test signatures may provide an alternative to FISH or immunohistochemistry-based tests.