Simple Summary: Prostate cancer is a prevalent cancer in men. Metastatic disease is initially responsive to androgen receptor signaling inhibition, but eventually resistance develops despite continuation of therapy. This resistance involves multiple adaptations in the cell but also to the tumor microenvironment, including epigenetic alterations. Epigenetic alterations change gene expression without DNA sequence modifications and play a key role as regulators of cell functions both in the tumor and the tumor microenvironment. Moreover, these epigenetic alterations highlight potential therapeutic targets. Targeting these epigenetic modifications could improve androgen receptor-targeted therapy and enhance anti-tumor immunity. In this review we discuss the role of epigenetics in prostate cancer, strategies to target them, and their impact on the tumor microenvironment, with the goal of identifying novel therapeutic avenues for advanced prostate cancer. Prostate cancer is the second most common cancer in men worldwide and is associated with high morbidity and mortality. Consequently, there is an urgent unmet need for novel treatment avenues. In addition to somatic genetic alterations, deviations in the epigenetic landscape of cancer cells and their tumor microenvironment (TME) are critical drivers of prostate cancer initiation and progression. Unlike genomic mutations, epigenetic modifications are potentially reversible. Therefore, the inhibition of aberrant epigenetic modifications represents an attractive and exciting novel treatment strategy for castration-resistant prostate cancer patients. Moreover, drugs targeting the epigenome also exhibit synergistic interactions with conventional therapeutics by directly enhancing their anti-tumorigenic properties by "priming" the tumor and tumor microenvironment to increase drug sensitivity. This review summarizes the major epigenetic alterations in prostate cancer and its TME, and their involvement in prostate tumorigenesis, and discusses the impact of epigenome-targeted therapies. [ABSTRACT FROM AUTHOR]