Influenza virus infection remains one of the largest disease burdens onhumankind.Influenza-associated bacterial co-infections contribute to severe disease andmortality during pandemic and seasonal influenza episodes.The mechanisms of severemorbidity following such bacterial co-infections mainly include failure of the antibacterialimmune response and synergy of the pathogens.Moreover,the failure of tolerance also isone of the main reasons for excessive mortality,which has been largely overlooked inanimal and human studies.In this review,advances in our understanding of the mechanismsof severe disease associated with bacterial co-infections following influenza virus infectionare discussed.Analysis of these mechanisms should help to develop novel approaches forthe prevention and treatment of influenza virus co-infections.