The “cytokine storm” (CS) consists of a spectrum of different immune dysregulation disorders characterized by constitutional symptoms, systemic inflammation and multiorgan dysfunction triggered by an uncontrolled immune response. Particularly in respiratory virus infections, the cytokine storm plays a primary role in the pathogenesis of respiratory disease and the clinical outcome of respiratory diseases, leading to complications such as alveolar edema and hypoxia. In this review, we wanted to analyze the different pathogenetic mechanisms involved in the various respiratory viral pandemics (COVID-19; SARS; MERS; H1N1 influenza A and Spanish flu) which have affected humans in this and last century, with particular attention to the phenomenon of the “cytokine storm” which determines the clinical severity of the respiratory disease and consequently its lethality.