The male reproductive and immune systems co-exist in a finely-balanced relationship. The spermatogenic cells are highly antigenic, and immune reactions against these cells and their supporting epithelia leads to inflammation of the reproductive tract, hypogonadism and infertility. Even worse, the male reproductive tract is open to the external environment, and is susceptible to a broad range of bacterial and viral infections, which demand an effective immune response. These infections may be transmitted through sexual activity (Neisseria gonorrhoeae, Chlamydia trachomatis) but more commonly, threats can arise from commensal organisms or blood-borne pathogens (E. coli, Coxsackievirus, Mumps, SARS-CoV). In fact, the balance is so fine that inflammation due to systemic infections or even inflammatory disease in other tissues compromises male reproduction, not least because inflammatory cytokines and other mediators inhibit the hypothalamic-pituitary-testis axis at all levels. So, how does the male reproductive system protect itself from the damaging effects of infection and inflammation, and what actually happens when things go wrong? In the past three decades, our understanding of these issues has increased dramatically. We now know that so-called “immunological privilege” of the testis involves active immunosuppression of antigen-presentation and T cell activation, while mechanisms of peripheral immune tolerance provide protection in the epididymis and remainder of the genital tract. These tissues possess a complex network of resident immune cells and immunoregulatory molecular pathways that serve the dual purpose of constraining immunity, while providing some degree of protection against infection. These complex mechanisms represent a fundamental, but frequently neglected, aspect of male reproductive health. In the face of the ever-expanding threat of infectious diseases, and emerging viruses more specifically, driven by climate change and global interconnectedness, and the as-yet unsolved mystery of rising male reproductive disorders and declining fertility world-wide, understanding these mechanisms has become crucial for preserving male health and well-being more broadly.