Marine sponges represent an excellent example of host-microbe symbiosis. Yet, most sponge-associated microorganisms remain uncultured, hampering efforts in determining interactions with their sponge host. This project aimed at enhancing our understanding of the sponge-bacteria interplay, focusing on both cultured and yet-uncultured sponge-associated lineages. Several novel sponge-associated taxa were elucidated by resolving their phylogeny and reconstructing their primary and secondary metabolism. Genome-based predictions revealed that the sponge microbiome mediates the interactions of the holobiont via heterotrophy, potential metabolite exchange and chemical defense. Sponge symbionts also possessed an extended genomic repertoire of defense systems implying adaptation to host environment. Moreover, genome mining for biosynthetic gene clusters (BGCs) and bioactivity screening of sponge-associated strains detected many candidate BGCs potentially involved in observed anticancer and antibacterial activity. Altogether, this work shed light into novel sponge-associated phylotypes, features that point at a symbiotic lifestyle and a rich secondary metabolite biosynthesis arsenal with biotechnological potential.