How neurons and neural networks, composed from highly dynamic molecules with relatively short half-lives, maintain stable firing properties remains one of the most fascinating questions in neuroscience. Since the time of Claude Bernard, scientists have been in pursuit of the fundamental principles and molecular mechanisms that underlie cellular, network and system-level homeostasis. Although intracellular Ca2+ has long been proposed as a feedback control signal, the source of Ca2+ and the molecular machinery enabling network-wide homeostatic responses remain largely unknown. In my talk, I will delve into the cellular and network properties actively regulated by the homeostatic system, the spatial scale of this control, and explore the role of mitochondria in maintaining activity set-points. Furthermore, I will present evidence of state-dependent dysregulation of activity set-points in familial Alzheimer’s models at the presymptomatic disease stage and introduce a novel mechanism that contributes to circuit-level resilience to Alzheimer’s disease pathology.