The immune system of higher vertebrates consists of two components: the innate and adaptive immunity. While the adaptive immune system relies on somatically generated and clonally selected antigen receptors, the innate immune system detects the presence of pathogens by their evolutionarily highly conserved, relatively invariant structural motifs. Interestingly, recent data suggest that activation of the innate immune system could play an important role in various diseases without the direct involvement of infectious pathogens. For example, a number of inflammatory cytokines, including TNF (tumor necrosis factor), IL (interleukin)-1β, IL-6 and IL-8, as well as iNOS (inducible nitric oxide synthase), all components of innate immunity, are also implicated in ischemia/reperfusion injury, and in the abnormal myocardial remodeling characteristic of chronic heart failure. Understanding of the regulation and activation of the innate immune system in diseases not obviously related to an immune response to specific pathogen could provide new therapeutic targets for cardiovascular diseases. Thus, in this review, we provide a general overview of the components of innate immunity with a focus on humoral factors, their role in the response to foreign pathogens, and their potential role in the response to tissue injury (i.e., the “Expanded Self-Non-Self” and the “Danger” theories of immune activation).