A conjugate vaccine against seven of the 91 known pneumococcal serotypes was licensed in the USA in 2000 and has had profound effects on pneumococcal disease and ecology. Among these is the virtual disappearance of vaccine serotypes from carriage, and their replacement with nonvaccine serotypes, some of which are making an impact upon pneumococcal disease. Here, the impact of this serotype replacement on pneumococcal disease is discussed, and those serotypes that are important players in the post-vaccine era are identified. Furthermore, the impact of replacement in vulnerable patient populations, such as Alaska Natives and persons living with HIV is discussed, as well as its consequences for other disease manifestations such as otitis media. Finally, lessons from the US experience for conjugate vaccination in other settings including sub-Saharan Africa are drawn.