Prostate cancer (PCa) has long been thought of as a disease with a heterogeneous phenotype. It can manifest in men as benign growths that can be safely watched or as more aggressive malignancies that can prove fatal. Recent investigations at the genomic, histopathological and molecular levels have identified tumor heterogeneity, the phenomenon of individual tumor cells presenting distinct genomic and phenotypic characteristics, as one of the most confounding and complex factors underlying PCa diagnosis, prognosis, and treatment. Despite tremendous progress made over the course of the last decade we still have an incomplete understanding of the extent and effect of intra- and inter-tumoral heterogeneity in the course of PCa progression. For example, a primary tumor can be classified into one of several molecular subgroups depending on whether the cancer has a particular gene fusion or a mutation which in turn might yield some patient-specific therapeutic regimen, but this same type of heterogeneous growth can be spatially or temporally restricted proving it difficult to detect during biopsy. We therefore present here a comprehensive review of the various studies addressing intra-tumor heterogeneity in PCa and in the context of that seen in other solid tumors. We discuss the impact of heterogeneity on clinical decision-making in treating both primary and metastatic lesions and how our understanding of this heterogeneity might help in developing better diagnostic tools and biomarkers and in guiding the selection of better therapeutic strategies. •Intra-tumor heterogeneity (ITH) in prostate cancer is a major confounding factor influencing disease progression.•Cancer stem cell, clonal (liner, braided river, or neutral), and punctuated-evolution models have been proposed to understand ITH.•Multifocal tumors in the prostate are common, and further challenge accurate prognosis.•Monoclonal origin and field effect hypotheses have been proposed to explain multifocality in prostate cancer.•ITH also plays a role in metastasis, and circulating tumor cell (CTC) and disseminated tumor cell (DTC) spread and survival.