Marine sponges are the source of numerous bioactive natural products that serve as chemical defenses and provide pharmaceutical leads for drug development. For some of the compounds, symbiotic bacteria have been established as the actual producers. Among the known sponge symbionts, 'Candidatus Entotheonella' members stand out because of their abundant and variable biosynthetic gene clusters (BGCs). Here, to obtain broader insights into this producer taxon, we conduct a comparative analysis on eight sponges through metagenomic and single-bacterial sequencing and biochemical studies. The data suggest sets of biosynthetic genes that are largely unique in 14 'Entotheonella' candidate species and a member of a sister lineage named 'Candidatus Proxinella'. Four biosynthetic loci were linked in silico or experimentally to cytotoxins, antibiotics and the terpene cembrene A from corals. The results support widespread and diverse bacterial roles in the chemistry of sponges and aid the development of sustainable production methods for sponge-derived therapeutics.