Interferon-alpha (IFN-alpha) is thought of by most immunologists as a fundamental component of the antiviral innate immune response, with other, accessory properties. Several lines of evidence point to a fundamental reappraisal of this conceptual framework because it may neglect other crucial functions of this cytokine under both health and disease conditions. Among these, a regulatory role in the inflammatory response is probably of paramount importance, as shown by in vivo and in vitro studies on humans, pets, and farm and laboratory animals. This role would not conflict with the main functions of IFN-alpha in the innate immune system and would complement these in line with major, evolution-based needs of the host. A hinge role of IFN-alpha between innate and adaptive immunity was recognized in the past on the basis of compelling evidence. This concept should now be widened; not only does IFN-alpha act to trigger, amplify, and sustain the different phases of the immune response, but it could also promote a substantial balance between danger and inflammatory response when an infectious challenge is either declining or completely over.