Innate immune sentinel cells must initiate and orchestrate appropriate immune responses for myriad pathogens. These stimulus-specific gene expression responses are mediated by combinatorial and temporal coding within a handful of immune response signaling pathways. We outline the scope of our current understanding and indicate pressing outstanding questions. The innate immune response is a first-line defense against invading pathogens and coordinates the activation and recruitment of specialized immune cells, thereby initiating the adaptive immune response. While the adaptive immune system is capable of highly pathogen-specific immunity through the process of genetic recombination and clonal selection, innate immunity is frequently viewed as a catch-all system that initiates general immune activation. In this review, we are re-examining this view, as we are distinguishing between immune sentinel functions mediated by macrophages and dendritic cells and innate immune effector functions mediated by cells such as neutrophils, NK cells, etc. Given pathogen diversity, including modes of entry, replication cycles, and strategies of immune evasion and spread, all successive waves of the immune response ought to be tailored to the specific immune threat, leading us to postulate that immune sentinel functions by macrophages and dendritic cells ought to be highly stimulus-specific. Here we review the experimental evidence for stimulus-specific responses by immune sentinel cells which initiate and coordinate immune responses, as well as the mechanisms by which this specificity may be achieved.