While lacking adaptive immunity, invertebrates maintain a very efficient innate immune system to combat an array of pathogens. Detecting and eliminating harmful microorganisms is accomplished by various proteins and signaling pathways that mediate this innate immunity. The operon concept is one of the major regulatory mechanisms that govern these immune responses in invertebrates. The first described operon model consists of the regulation of a cluster of genes whose expression is co-regulated and co-expressed under the control of a single promoter and regulatory elements of prokaryotic organisms. All of these regulatory systems are found in invertebrate immunity in the context of expression of immune-related genes, specifically antimicrobial peptides (AMPs), pattern recognition receptors (PRRs) and the set of other immune effector molecules. The operon model is critical to quickly and efficiently activate immune responses to a pathogen detection. The model puts together the expression of multiple immune genes, which enables invertebrates to rapidly build a broad immune defense. Here, immune genes are considered as an example within the concept of operon to review how operon influences immune gene regulation in invertebrates using arthropods, mollusks, annelids, and other phyla in particular (Table 4.1).