Animals are exposed to changes in their environmental conditions daily. Such changes will become increasingly more erratic and unpredictable with ongoing climate change. Responses to changing environments are influenced by the genetic architecture of the traits under selection and modified by a range of physiological, developmental, and behavioural changes resulting from phenotypic plasticity. Furthermore, the interactions between multiple environmental stressors to which organisms are exposed can generate unexpected phenotypic responses. Understanding how genetic and plastic variation contributes to the response to combined environmental stress will be key to predicting how animals will cope with climate change and ultimately will define their ability to persist. Here, we review the approaches used to explore how animals respond to combined stressors, specifically nutrition and temperature, the physiological mechanisms that underlie such plastic responses, and how genetic variation alters this plasticity.