Metabolic syndrome (MetS) is a clustering of metabolic complications representing a pre-morbid condition that is a substantial public health burden. Animal models provide an opportunity to examine correlations among different metabolic parameters to understand why metabolic complications sometimes cluster and sometimes do not. This chapter provides an overview of animal models of MetS that are used to understand etiology and pathophysiology, with a focus on methods of identifying and testing candidate genes with the aim of translating results to human studies. Genetic, epigenetic, environmental, and gene by environmental methods and results are discussed along with important lessons learned. Rodent models are the most frequently used, however other animal models including dogs, pigs, sheep, and non-human primates have contributed to our understanding of MetS and each are discussed. Additionally, animal models used to test physiological hypotheses are reviewed along with their potential to illuminate DNA sequence–metabolic function relationships to inform therapies.