The search for new bioactive natural products (NP) has prompted scientists to exploit environmental niches in which the production of these compounds is ecologically motivated. Microbial predator-prey interactions are particularly rich sources of natural products. We describe one such interaction in which bacterivorous amoebae and their prokaryotic prey meet. Amoebae are voracious and ubiquitous predators to bacteria, hence, we study bacterial NP-based defense strategies to evade amoebal predation. We describe a variety of natural products that show amoebicidal activity along with investigations into their biosynthesis, regulation, and synergistic activities.