The innate immune system accounts for the fastest defense response to microbial invasion although, conversely, several pathogens can modulate the host response resulting in a modulation of their survival and propagation. In this regard, some bacterial toxins possess immuno-stimulating properties that have been exploited in terms of vaccine adjuvanticity and induction of specific cytotoxic T lymphocytes. Among these, Bordetella pertussis toxin (PTX) possesses the ability of modulating the immune responses in multiple ways, as demonstrated in vivo as well as in ex-vivo and in vitro experimental systems. In addition, PTX, as well its nontoxic B-oligomer PTX-B and the genetically inactivated PT-9K/129G molecule, have been recently shown to inhibit infection of primary cells, lymphoid organs and cervical tissue by the human immunodeficiency virus type 1 (HIV-1), the etiological agent of the acquired immunodeficiency syndrome. This article focuses on the regulation of the immune response and on the anti-viral properties of PTX and of its nontoxic related molecules as an example of exploitation of a natural bacterial product to combat viral infections.