The evolution of intracellular pathogens is considered in the context of ambiguities in basic definitions and the diversity of host-microbe interactions. Intracellular pathogenesis is a subset of a larger world of host-microbe interactions that includes amoeboid predation and endosymbiotic existence. Intracellular pathogens often reveal genome reduction. Despite the uniqueness of each host-microbe interaction, there are only a few general solutions to the problem of intracellular survival, especially in phagocytic cells. Similarities in intracellular pathogenic strategies between phylogenetically distant microbes suggest convergent evolution. For discerning such patterns, it is useful to consider whether the microbe is acquired from another host or directly from the environment. For environmentally acquired microbes, biotic pressures, such as amoeboid predators, may select for the capacity for virulence. Although often viewed as a specialized adaptation, the capacity for intracellular survival may be widespread among microbes, thus questioning whether the intracellular lifestyle warrants a category of special distinctiveness.