The term hormesis has been adopted to explain how a mild stress can result in favorable adaptations that protect the body against more severe stresses and disorders derived from physical stress or other reasons. Generation of reactive oxygen species (ROS) is a ubiquitous phenomenon associated with aerobic life. If not adequately kept in check, ROS generation may result in oxidative stress that can elicit oxidative damage, disease, and aging, as well as deterioration of functional performance of the organs, and some of the damages may be permanent. However, research literature has shown a remarkable resilience of the organism to deal with ROS, mainly due to the upregulation of cellular antioxidant defense system (Ji 1995). Organisms may also make certain subcellular remodeling to reduce ROS generation through more efcient use of oxygen (i.e., reducing ROS while maintaining the same metabolic rate). A good example might be mitochondrial biogenesis and remodel (Chan 2006; Handschin and Spiegelman 2008). These adaptations could occur in response to many physiological, environmental, and pathological stresses, but the current chapter will mainly focus on a unique metabolic stress animals encounter to maintain mobility to seek food, reproduction, and survival, namely physical activity through muscle contraction.