Following the discovery of endotoxins by Richard Pfeiffer, such bacterial product was associated to many severe disorders produced by an overwhelming inflammatory response and often resulting in endotoxic shock and multiple organ failure. However, recent clinical and basic sciences investigations claimed some beneficial roles of typical as well as atypical endotoxins. The aim of this paper is to focus on recent data supporting a beneficial activity of both typical and atypical endotoxins. Such novel perspective looks promising for development of new drugs for prevention and therapy of several human diseases.