While doctors have made advances in the early detection and treatment of prostate cancer since Dr. Huggins first treated men with hormonal therapy, there are still outstanding questions. First, how can we differentiate between aggressive and indolent prostate cancer? Doctors are excellent at identifying men who require aggressive therapies immediately, and they are also able to identify men who have very slow growing cancers, however there are ‘Men in the Middle’ who fall in between those two categories. Doctors need better tools to identify which Men in the Middle will progress to lethal disease and which could be spared the life-altering side effects of treatment. Second, why is prostate cancer so common compared to other male urological cancers? As the androgen receptor pathway is developmentally critical, we hypothesized that other developmental pathways may also play a key role in oncogenesis and tumor progression. In this study, we demonstrate that the caudal Müllerian duct mesenchyme (CMDM) is able to drive prostate epithelial differentiation and is a key determinant driving cell lineage specification between urethral glands and prostate epithelia. These results help to explain key developmental differences between prostate and urethral gland differentiation, and provide support to investigate how factors secreted by the caudal Müllerian duct may be involved in prostate disease prevention and treatment. Our lab recently identified differentially regulated gene networks between the prostate and seminal vesicle, and has used these data to determine prognostic cancer gene-centered biomodules specific to the prostate. One such signaling module to emerge was the MEIS/HOX axis. MEIS and HOXB13 proteins have critical roles in normal proliferation and cell-fate determination in prostate development, so it is logical that their roles could be exploited in cancer. In this work, we hypothesize that MEIS proteins function as tumor suppressors in advanced prostate cancer. Our work indicates that prostate cancer patients with high levels of MEIS expression survive longer than men with lower expression. Our laboratory’s work is the first to implicate the importance of MEIS proteins in prostate cancer. My work provides the levels and distribution of MEIS isoforms in the normal and cancerous prostate, ultimately helping the burgeoning field of MEIS/HOX investigation move ahead, as well as providing new areas of investigation for both the developmental and cancer biology fields.