<p>Animal models remain an indispensable bridge between basic discovery and clinical translation for chronic, multi-factorial diseases. This comparative review synthesizes current evidence on the use of rodents, large non-rodents, and non-mammalian organisms in modelling cancer, cardiovascular disorders, diabetes and obesity, hypertension, chronic kidney and liver diseases, and emerging respiratory infections such as COVID-19. The review examine how induced, spontaneous, genetically modified, control, and healthy models recapitulate human pathophysiology. The review draws attention to the alternatives in models with consideration of affordability, ethical limitations, ease of genetic modification, and biological integrity. Rodents (e.g., C57BL/6 mice, Zucker and Goto-Kakizaki rats) dominate pre-clinical pipelines owing to short generation times and well-defined genomes, yet large animals including pigs, dogs, and non-human primates offer superior anatomical and pharmacokinetic congruence for late-stage efficacy and safety studies. Zebrafish, Drosophila, and <i>C. elegans</i> accelerate high-throughput screens and illuminate conserved molecular networks, while species such as ferrets and cats uniquely model respiratory-virus transmission dynamics. Across disease categories, no single species recapitulates the complete human spectrum; therefore, convergent evidence from complementary models is essential. We also integrate evolving regulatory frameworks (ARRIVE 2.0, PREPARE, and the FDA Animal Rule) that enforce rigor, reproducibility, and welfare, and we discuss emerging genome-editing and humanized-organ technologies poised to refine or replace traditional models. Altogether, the review underscores a decision matrix that matches research objectives with the most predictive, ethically justifiable model, thereby streamlining translational trajectories and reducing attrition in drug development for chronic diseases.</p> Graphical Abstract <p></p>