The diagnosis of prostate cancer is based on microscopic criteria. Presently, prostate needle biopsy interpretation can be a challenge for the pathologist due to the increased number of specimens with limited amount of suspicious glands and minimal atypia. It is critical for the pathologist to have an organized methodical approach when considering the morphological features enabling a definitive diagnosis of prostate cancer. Although several diagnostic criteria and supportive features have been advocated, only few findings are absolutely specific and diagnostic of prostate cancer. The diagnosis of prostate cancer relies on a combination of architectural and cytological features that are reviewed in detail herein. Infiltrative growth pattern, prominent nucleoli and lack of basal cells are the most useful diagnostic criteria. Perineural invasion, glomerulation and mucinous fibroplasia are pathognomonic features of prostate cancer, although uncommon on small prostate cancer foci. The role of immunohistochemistry in establishing a diagnosis of limited prostate is addressed.