Spontaneous physical activity (SPA) behavior, or the drive to move, is initiated by brain centers and could therefore be therapeutically targeted. A major goal of our work is to understand the brain circuitry driving SPA, so that obesity therapies based on SPA can be considered. The neuropeptide orexin is part of the circuitry driving SPA. I will discuss our work using animal models to study the impact of orexin loss and gain, as well as natural variation in SPA, I will also present work on proof of concept studies for orexin therapeutic interventions for obesity using chemogenetics for orexin.