Symbioses with bacteria are critical to animal function, and marine sponges are excellent exemplars of the intimacy of such partnerships. Using extensive genomic and biological resources available for the Great Barrier Reef sponge Amphimedon queenslandica and its low complexity bacterial symbiont community, we are taking a multifacted approach to explore the nature of interactions between the partners. Transcriptional, cellular and metabolic modeling analyses reveal high fidelity relationships that are mediated by conserved gene pathways that suggest an ancient interplay between innate immunity and metabolic homeostasis in animal-bacterial crosstalk.