While type I interferons (IFNs) are universally acknowledged for their antiviral and immunostimulatory functions, there is increasing appreciation of the detrimental effects of inappropriate, excessive, or mistimed type I IFN responses in viral and bacterial infections. The underlying mechanisms by which type I IFNs promote susceptibility or severity include direct tissue damage by apoptosis induction or suppression of proliferation in tissue cells, immunopathology due to excessive inflammation, and cell death induced by TRAIL- and Fas-expressing immune cells, as well as immunosuppression through IL-10, IL-27, PD-L1, IL-1Ra, and other regulatory molecules that antagonize the induction or action of IL-1, IL-12, IL-17, IFN-γ, KC, and other effectors of the immune response. Bacterial superinfections following influenza infection are a prominent example of a situation where type I IFNs can misdirect the immune response. This review discusses current understanding of the parameters of signal strength, duration, timing, location, and cellular recipients that determine whether type I IFNs have beneficial or detrimental effects in infection.