Bacterial diseases cause significant economic loss to the aquaculture industry. Antibiotic resistance calls for new solutions alternative to antibiotics. CLCA genes are well conserved across species and are of interest due to their physiological and pathological significance. CLCAs are expressed in various tissues, including mucosa, epithelium, and endothelium. Mucus is the first line of defense for a fish living in a complex environment . Fish mucus has metalloproteases that act as antibacterial peptides. Certain CLCA family members are stress-inducible zinc metalloproteases in higher organisms. We characterized the CLCA gene family members in various fish species and identified the metal-binding motif HEXXH in most fish CLCAs. We also found significant CLCAs induction in response to bacterial infection in channel catfish and zebrafish. Interestingly, we find that CLCAs are secreted into the mucus and other tissues along with other stress- inducible factors suggesting an essential role in fish immunity. Our other data indicate that the soluble isoform of fish CLCA acts as a potential antibacterial peptide or an immune activator.