During the long history of co-evolution with protists, bacteria have evolved defense strategies to avoid grazing and survive phagocytosis. These mechanisms allow bacteria to exploit phagocytic cells as a protective niche in which to escape from environmental stress and even replicate. Importantly, these anti-grazing mechanisms can function as virulence factors when bacteria infect humans. Here, we discuss how protozoan predation exerts a selective pressure driving bacterial virulence and shaping their genomes, and how bacteria-protist interactions might contribute to the spread of antibiotic resistance as well. We provide examples to demonstrate that besides being voracious bacterial predators, protozoa can serve as melting pots where intracellular organisms exchange genetic information, or even “training grounds” where some pathogens become hypervirulent after passing through. In this special issue, we would like to emphasize the tremendous impact of bacteria-protist interactions on human health and the potential of amoebae as model systems to study biology and evolution of a variety of pathogens. Besides, a better understanding of bacteria-protist relationships will help us expand our current understanding of bacterial virulence and, likely, how pathogens emerge.