Central to the biology of many pathogenic bacteria are a number of specialized machines, known as type III, type IV, or type VI protein secretion systems. These machines have specifically evolved to deliver bacterial effector proteins into host cells with the capacity to modulate a variety of cellular functions. The identification of the biochemical activities of many effector proteins, coupled with a better understanding of their potential contribution to pathogenesis, has revealed common themes in the evolutionary design and function of these remarkable bacterial proteins.