This review focuses on genes required for resistance to mouse cytomegalovirus (MCMV), as identified through unbiased genetic screening. Components of the developmental, sensing, and effector pathways, functioning in multiple cell types, were detected by infecting 22,000 G3 mutant mice with MCMV at an inoculum easily contained by WT animals. Merging these findings with discoveries from hypothesis-based studies, we present a cohesive picture of the essential elements utilized by the mouse innate immune system to counter MCMV. We believe that many breakthrough discoveries will yet be made using a classical genetic approach.