The microorganisms that cause infectious diseases have a way of humbling us. Just as we think we have a problem solved, the microbes outsmart us. Penicillin was a miracle in 1943 when it was first mass produced. By 1947 the bacteria had already developed penicillin resistance. We are always behind in the game we play with influenza virus every year, trying to pick the right strains for the vaccine. We thought we could handle pertussis by making a vaccine, and that we did, starting with a whole-cell vaccine in the 1940s followed by an improved acellular vaccine in the 1990s with fewer adverse effects. Oh, but wait. Why is pertussis coming back with a vengeance in the United States with a record number of cases in 2014? The “improved” acellular vaccines, although certainly associated with fewer adverse effects than the original whole-cell versions, do not work as well. With us once again outsmarted, pertussis is back.