Advances in genetic engineering and metabolic imaging are transforming our ability to probe brain function with unprecedented precision. This chapter explores how the integration of optogenetics, chemogenetics, and genetically encoded biosensors with functional magnetic resonance spectroscopy (fMRS) enables dynamic, cell-type-specific interrogation of brain metabolism in animal models. Building on foundational concepts, such as the astrocyte–neuron lactate shuttle, the malate–aspartate shuttle, and the glutamate–glutamine–GABA cycle, we highlight the limitations of classical frameworks in explaining fast, stimulus-locked metabolic changes captured by modern fMRS techniques. We discuss emerging analysis methods inspired by functional MRI—including glutamate response functions and general linear modeling—that are redefining how fMRS data are interpreted. Finally, we argue that the synergy between genetic control, real-time metabolic monitoring, and computational modeling is ushering in a new era of mechanistic, quantitative neuroenergetics, with profound implications for understanding both normal brain function and metabolic pathology.