Organisms living in urban environments are exposed to many novel, sometimes beneficial, but most often challenging conditions. These conditions include increased exposure to chemical pollution, artificial light at night, noise, altered pathogen and predator communities, increased abundance of often poor quality food, increased temperature, and increased human presence and disturbances. Given the central role of a variety of physiological responses in coping with challenges such as these, the authors of the chapter expect that the range of physiological phenotypes expressed by individuals and species will dramatically influence their ability to persist in urban habitat and cope with urban challenges. They also expect that plasticity in components of these physiological systems will be an important target of selection imposed by the challenges confronting urban populations. The chapter takes a closer look at three fundamental physiological systems in animals that are central components of coping responses to environmental challenges, namely detoxification, and endocrine and metabolic systems.