AMPK is an evolutionary conserved energy sensor involved in the regulation of energy metabolism. Based on biochemical studies, AMPK has brought much of interest in the recent years due to its potential impact on metabolic disorders. Suitable animal models are therefore essential to promote our understanding of the molecular and functionnal roles of AMPK but also to bring novel information for the development of novel therapeutic strategies. The organism systems include pig (Sus scrofa), mouse (Mus musculus), fly (Drosophila melanogaster), worm (Caenorhabditis elegans) and fish (Danio rerio) models. These animal models have provided reliable experimental evidence demonstrating the crucial role of AMPK in the regulation of metabolism but also of cell polarity, autophagy and oxidative stress. In this chapter, we update the new development in the generation and application of animal models for the study of AMPK biology. We also discuss recent breakthroughs from studies in mice, fly and worms showing how AMPK has a primary role in initiating or promoting pathological or beneficial impact on health.