Anemonefish and host sea anemones have one of the most iconic symbiotic relationships, which has existed for at least 12 million years. This relationship is quite rare, with 28 different species of anemonefish living symbiotically with only ten out of over 1700 species of sea anemones. Crude sea anemone extracts and venom exhibit anti-cancer and anti-microbial properties. We used a proteotranscriptomics approach on the most popular host anemone Entacmaea quadricolor to investigate this symbiosis and to catalogue this potential drug development arsenal. Milked venom was a complex mixture containing 2,736 proteins. While E. quadricolor tentacles expressed RNA transcripts for diverse toxins (n=1251) only 10% were found in the venom (n=135) highlighting the perils of using transcriptomics alone to determine the dominant venom phenotype. We also found that neurotoxin tentacle transcripts and proteins in venom responsible for membrane damage, pore formation, and paralysis that could be potential drug leads were downregulated when E. quadricolor hosted Amphiprion percula. Many toxins were difficult to categorize as they contained multiple functional domains and several protein scaffolds not observed previously. Intriguingly, the tentacle transcriptome, contained 300 gene clusters with one or more Immunoglobulin(IG)-like domains and 33 of these appeared in venom, making IG-like proteins the largest toxin component in the venom. Similar IG-like proteins have been described as natural venom inhibitor proteins, including proteins known to neutralise snake venom metalloendopeptidases and phospholipases. More importantly these natural inhibitor-like Ig proteins were upregulated in the presence of anemonefish. In summary our study reveals for the first time that host sea anemones adjust their production and expression of toxins to play an active role in establishing and maintaining their symbiotic relationship with anemonefish. This work will be used to inform future investigations into anemonefish toxin resistance and will provide several new protein toxin scaffolds for drug development.