Secondary pulmonary infections by encapsulated bacteria including Streptococcus pneumoniae and Staphylococcus aureus following influenza represent a common and challenging clinical problem. The reasons for this polymicrobial synergy are still not completely understood, hampering development of effective prophylactic and therapeutic interventions. Although it has been commonly thought that viral-induced epithelial cell damage allows bacterial invasiveness, recent studies by several groups have now implicated dysfunctional innate immune defenses following influenza as the primary culprit for enhanced susceptibility to secondary bacterial infections. Understanding the immunological imbalances that are responsible for virus/bacteria synergy will ultimately allow the design of effective, broad-spectrum therapeutic approaches for prevention of enhanced susceptibility to these pathogens.