Canine Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine and a central member of the IL-6 cytokine family—including IL-6, IL-11, IL-27, IL-31, leukemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), and cardiotrophin-like cytokine factor 1 (CLCF1)—all of which signal through receptor complexes utilizing the shared gp130 subunit to activate JAK/STAT and MAPK pathways. In dogs (Canis lupus familiaris), IL-6 regulates acute-phase protein production (such as C-reactive protein and serum amyloid A), B- and T-cell differentiation, hematopoiesis, and systemic inflammatory responses. Elevated IL-6 levels are associated with infectious diseases including canine parvovirus, distemper, and sepsis, as well as chronic inflammatory and immune-mediated disorders, osteoarthritis, and neoplasia. Importantly, several naturally occurring canine diseases serve as translational models for human conditions in which IL-6 plays a pathogenic role, including canine osteosarcoma (model for pediatric osteosarcoma), lymphoma (model for non-Hodgkin lymphoma), melanoma, atopic dermatitis (model for allergic skin disease), inflammatory bowel disease (model for human IBD), rheumatoid-like immune-mediated polyarthritis, and dilated cardiomyopathy. Dysregulated IL-6 signaling in these conditions contributes to inflammation, tumor progression, and systemic pathology, making canine IL-6 a critical biomarker and therapeutic target in veterinary medicine and a valuable component of comparative and translational research.