Prostate cancer is the most common malignancy and the second leading cause of cancer death in American men. One of the most intriguing aspects of prostate cancer is that despite the similar high incidence of latent forms of prostate cancer detected in men throughout the world, remarkable disparity exists in the rate of clinical progression of this disease. Men living in North America have significant disease progression, whereas men living in Japan or China do not. In this article, the potential epigenetic factors that may play a critical role in determining the rate of prostate cancer growth and progression is discussed. We propose that stromal-epithelial interaction may be of fundamental importance to prostate cancer growth and expression of its invasive phenotypes. Furthermore, we have demonstrated that delivering appropriate growth factor(s) and/or extracellular matrice(s) to an established non-tumorigenic prostatic epithelial cell line (but not normal prostatic epithelial cells) may accelerate disease progression and may irreversibly affect prostatic epithelial cell behavior.