It is surprising that despite the prevalence of prostate disease, little is known about the immunobiology of the prostate and its contribution to disease. The prostate is the target of many diseases like infection of the prostate gland, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), benign hyperplasia and cancer. In this review we will focus on the relationship of the immune system with the prostate gland in two different scenarios: in the first one, the question of how prostate epithelial cells deal with inflammatory stimuli, like microorganisms, is addressed. Whereas the role of infiltrating innate immune cells like macrophages and neutrophils in prostate inflammation has been extensively studied, the particular contribution of prostate epithelial cells to an inflammatory setting has barely been investigated. Prostate epithelial cells can act as early sensors of infection, expressing Toll like receptors, the best well known innate immune receptors. Thus they become sentinels of the prostate gland, like the epithelial cells of other internal organs. The way these cells respond to infection up-regulating pro-inflammatory mediators is discussed. This topic is of particular interest since chronic inflammation has been postulated to be an important driving force to prostate carcinoma. In the second scenario, the situation in which the prostate gland becomes a target of an autoimmune response is analyzed. Chronic inflammatory prostate disease of noninfectious origin seems to be a good example of this situation, since at least 30% of the patients suffering from CP/CPPS exhibited IFN-γ-secreting, proliferating lymphocytes against prostate antigens such as prostatic acid phosphatase (PAP), prostate specific antigen (PSA), and other antigens present in prostate homogenates and seminal plasma. We have dissected the immunological mechanisms that are involved in these patients and in experimental models of autoimmune prostatitis as well as analyzed its consequences on the fertility of these patients.