Type I interferons (IFNs) are pleiotropic cytokines well recognized for their role in the induction of a potent antiviral gene program essential for host defense against viruses. They also modulate innate and adaptive immune responses. However, the role of type I IFNs in host defense against bacterial infections is enigmatic. Depending on the bacterium, they exert seemingly opposite and capricious functions. In this review, we summarize the effect of type I IFNs on specific bacterial infections and highlight the effector mechanisms regulated by type I IFNs in an attempt to elucidate new avenues to understanding their role.