A balanced intake of different classes of nutrients is a key determinant of health, wellbeing, and aging. We want to understand how animals decide what to eat and how these decisions affect the physiology of the animal. To achieve a mechanistic, integrated, whole-animal understanding of nutritional decision-making we work at the interface of behavior, metabolism, microbiome, and physiology in the adult Drosophila melanogaster. I will discuss how the powerful combination of neurogenetics, automated, quantitative behavioral analyses, nutritional and microbial manipulations, and activity imaging approaches is allowing us to achieve a mechanistic understanding of how neuronal circuits interact with organ systems and the microbiome to implement proto-cognitive behaviors and regulate them according to internal states. Adapting nutrient specific appetites to the needs of the animal allows these to optimize important traits such as aging and reproduction.