In spite of recent developments in diagnosis, staging and treatment, most patients with advanced prostate cancer will ultimately progress from androgen-sensitive to an irreversible castration-resistant disease. These androgen-independent cancers frequently give rise to widespread metastasis, dramatically reducing the median survival of patients (Tannock et al, N Engl J Med, 351(15):1502-1512, 2004) and accounting for more than 32, 000 deaths/year in USA (Jemal et al, CA Cancer J Clin, 60:277-300, 2010), which correspond to over 90 % of PC related mortality (Man, Gardner, Int J Biol Sci, 4(4):246-258, 2008). It is a common belief that cancer metastasis result from a multi-stage nonrandom process characterized by intricate interactions between cancer cells and the host microenvironment, leading to the detachment of cancer cells from their tissue of origin, their dissemination through the bloodstream and to invasion of the target metastatic site (Patel et al, Future Oncol, 7(11):1285-1297, 2011). Metastasis represents yet one of the most enigmatic aspects of prostate cancer pathogenesis, in which a cascade of proteolytic enzymes, inflammatory cytokines, growth factors, activated oncogenes, oxidative stress and hypoxia linked proteins and adhesion molecules, orchestrate a continuous loop that enable migrating cancer cells detached from the primary tumor bulk, to survive and proliferate in an adverse remote body microenvironment. In this chapter, we discuss the nature and alterations of the signaling pathways involved in the development of prostate cancer metastasis, reporting the current status of knowledge on the changes occurring either in prostate cancer cells and in tumor-associated stromal tissue, with particular emphasis to the process of epithelial-mesenchymal transition (phenotypic plasticity) and to the role of cancer stem cells in prostate cancer progression and metastasis. We will highlight, also, the emerging data concerning new therapeutic targets for treatment of metastatic prostate cancer that, while deserving further inquiry, look very promising to improve our chances to successful approach the advanced disease or, even, primarily reduce the risk of metastasis from castration-resistant prostate cancer (Vashisht, Bagler, PLoS One, 7(11):e49401, 2012)