Substantial progress has been made throughout the last decades in the elucidation of the key players and mechanisms responsible for Ca2+ signal generation in both excitable and non-excitable cells. Importantly, these studies led also to the recognition that a close correlation exists between the deregulation of cellular Ca2+ homeostasis and the development of several human pathologies, including neurodegenerative disease. Notwithstanding this advances, much less is certain about the targets and mechanisms by which compromised Ca2+ signaling exerts its effects on cell function and survival. Recently it has been proposed that deregulation of cellular energy metabolism and protein turnover (synthesis, folding and degradation) are also fundamental pathomechanisms of neurodegenerative disease, pointing to the pivotal role of autophagy, a major cellular pathway controlling metabolic homeostasis. Indeed, activation of autophagy has been shown to represent a highly successful strategy to restore normal neuronal function in a variety of models of neurodegenerative disease. Here we review recent advances in elucidating Ca2+ regulation of autophagy and will highlight its relationship to neurodegeneration.