All animals are inhabited by bacteria, and maintaining homeostasis in the multicellular environment of the host involves the complex balancing act of promoting the survival of symbionts while defending against intruders. Sponges (Porifera), in addition to housing diverse bacterial symbiont assemblages, also rely on bacteria filtered from the water column for nutrition. My research uses the genome-enabled demosponge, Amphimedon queenslandica, a member of one of the earliest-diverging animal phyletic lineages, as an experimental platform to investigate the genomic toolkit underpinning animal-bacteria interactions. Using comparative bioinformatics tools, I characterised a surprisingly large and complex repertoire of innate immune receptors from the NLR family of genes encoded in the A. queenslandica genome. I then used a high throughput RNAseq approach to profile the sponge's global transcriptomic response to foreign versus its own native bacteria. Conserved metazoan innate immune pathways were activated in response to both foreign and native bacteria. However, only the native bacteria elicited the expression of a more extensive suite of signalling pathways, involving TGF-β signalling and the transcription factors NF-κB and FoxO. Upregulation of the nutrient sensor AMPK in all treatments along with immune signalling genes, which all regulate FoxO activity, further suggests an interplay between metabolic homeostasis and immunity. Finally, I used microscopy to track the cellular-level processing of the different bacteria by the sponge. Consistent with the observed transcriptional response, the native bacteria were ingested by archaeocytes more rapidly than the foreign bacteria. The slower processing of foreign bacteria also correlated with the expression of numerous Nrf2-associated detoxification genes, indicative of cellular stress, only in response to foreign bacteria.iii Deciphering the genomic tool-kit underlying animal-bacteria interactions