Predation is a driving force of organismal ecology and evolution. Predator-prey interactions, constrained by other environmental factors and historical contingency, shape physical and behavioral phenotypes of organisms on both sides of the interaction arrow. Yet despite the universality of trophic interactions in biology, study of the ecology and evolution of anti-predator defense is challenging because these interactions tend to be brief and unpredictable, and thus gathering direct evidence requires patience and serendipity. The evolution of prey defenses can be studied by DNA sequencing followed by phylogenetic analysis, and the ecology can be studied by field observation and bringing tractable systems into the lab. However, animal models generally do not allow genetic manipulation, strict control of environmental variables, or detailed observation of evolution in real time, all of which are important for demonstrating evolutionary causes and consequences. Developing complementary microbial predator-prey systems can help overcome this hurdle. There is an extensive body of work on microbial experimental evolution, and many microbes come with well-characterized genomes and established methods for genetic manipulation. As understanding of microbial ecology and the mechanisms of their trophic interactions grows apace, these systems are poised to make valuable contributions to our understanding of how predator behaviors evolve, why certain anti-predator defenses evolve and not others, and how multiple defenses function together in a single defense portfolio. These systems will enable us to both test hypotheses formulated from the study of larger organisms and to propose new ones that can be tested in larger organisms with existing methods.