Within the past 5 years, research has increasingly addressed molecular alterations in prostate cancer (CaP). Mutations of tumor suppressor gene p53 have been found in a variety of cancers, including urologic neoplasms. Several studies have been conducted on CaP specimens, citing frequencies of p53 alterations in localized cancers ranging from 4 to 60% and with more advanced hormone refractory disease, as high as 94%. The majority of studies have revealed a low percentage of p53 abnormalities in early-stage (clinically organ-confined) CaP. The overwhelming bulk of evidence suggests that the frequency of p53 abnormalities does increase with disease progression and is highest in tissues from patients with hormone-refractory prostate cancer. More recently, our group and others have found that focal p53 expression in the primary tumor by immunohistochemistry is predictive of cancer recurrence after radical prostatectomy. bcl-2 is an oncogene critically involved in the apoptosis, or programmed cell death. Overexpression of bcl-2 protein by immunohistochemistry has been commonly detected in advanced hormone refractory CaP. Our group recently has also shown that bcl-2 protein expression in primary CaP is a predictor of cancer recurrence after radical prostatectomy. Furthermore, the combination of p53 and bcl-2 protein expression were both independent predictors of recurrence after surgery. Most recently, we have shown that even though p53 and bcl-2 are predictive biomarkers when sampling the radical prostatectomy specimen, they are not useful to predict postoperative recurrence when sampling the pretreatment needle biopsy. Ki-67 is an antigen of cellular proliferation. Immunohistochemical staining for Ki-67 in archival material can be performed using the MIB-1 antibody. Unlike our results with p53 and bcl-2, Ki-67 protein expression by immunohistochemistry using MIB-1 was not an independent prognostic marker for cancer recurrence after radical prostatectomy although it may have clinical utility in subsets of patients. Assessment of MIB-1 staining in CaP needle biopsy samples is underway. Tumor neovascularity, or angiogenesis, is necessary for cancers to grow and metastasize. Angiogenesis in CaP as a prognostic marker has received recent attention. Most studies have used factor VIII immunohistochemical staining and increased angiogenesis has been suggested as a staging and prognostic marker. Our group has recently conducted a large study of radical prostatectomy patients and used CD34 antigen immunohistochemistry to assess neovascularity. We did not find that this biomarker assessment was an independent prognostic marker of cancer recurrence after radical prostatectomy. Further work is being conducted in needle biopsy samples. More research is needed to assess new biomarkers and, most importantly, to standardize the methodology for sampling and assaying biomarkers in heterogeneous and multifocal prostate cancer.