The epididymis is known to be exposed to a constant risk of inflammatory conditions resulting from bacterial infections, or from idiopathic and noninfectious causes. A common result of these conditions is epididymitis, a pathology that may lead to the destruction of the epididymal duct and transient or permanent sterility. The negative impact of epididymitis on semen quality and fertility justifies the need for a better understanding of cellular and molecular mechanisms by which innate immunity is modulated in the epididymis and the pathophysiology of this clinical condition. Our laboratory has been interested in the last years in the cellular and biochemical events involved in the epididymal defense response against a bacterial challenge, as well as in how these responses are integrated by glucocorticoids and the glucocorticoid receptor. We have been also interested in naturally occurring antimicrobial proteins secreted by the epididymis. Antimicrobial proteins are known to be part of the innate immune system, with potential biological role during a defense response against invasion by pathogens in the epididymis. Here we review the expression and regulation of antimicrobial proteins, particularly beta-defensins in the epididymis, highlighting isoforms of the beta-defensin-like SPAG11B gene. Aspects of their broad range of biological roles and potential use as targets to help to prevent or treat diseases, such as epididymitis, are also discussed