Low-cost, high-throughput nucleic acid sequencing ushered the field of microbial ecology into a new era in which the microbial composition of nearly every conceivable environment on the planet is under examination. However, “static” screenshots derived from sequence-only approaches belie the underlying complexity of the microbe-microbe and microbe-host interactions occurring within these systems. Reductionist experimental models are essential to identify the microbes involved in interactions and to characterize the molecular mechanisms that manifest as complex host and environmental phenomena. Herein, we focus on three models (Bacillus-Streptomyces, Aliivibrio fischeri-Hawaiian bobtail squid, and gnotobiotic mice) at various levels of taxonomic complexity and experimental control used to gain molecular insight into microbe-mediated interactions. We argue that when studying microbial communities, it is crucial to consider the scope of questions that experimental systems are suited to address, especially for researchers beginning new projects. Therefore, we highlight practical applications, limitations, and tradeoffs inherent to each model.