The calcium ion (Ca(2+)) is the main second messenger that helps to transmit depolarization status and synaptic activity to the biochemical machinery of a neuron. These features make Ca(2+) regulation a critical process in neurons, which have developed extensive and intricate Ca(2+) signaling pathways. High intensity Ca(2+) signaling necessitates high ATP consumption to restore basal (low) intracellular Ca(2+) levels after Ca(2+) influx through plasma membrane receptor and voltage-dependent ion channels. Ca(2+) influx may also lead to increased generation of mitochondrial reactive oxygen species (ROS). Impaired abilities of neurons to maintain cellular energy levels and to suppress ROS may impact Ca(2+) signaling during aging and in neurodegenerative disease processes. This review focuses on mitochondrial and endoplasmic reticulum Ca(2+) homeostasis and how they relate to synaptic Ca(2+) signaling processes, neuronal energy metabolism, and ROS generation. Also, the contribution of altered Ca(2+) signaling to neurodegeneration during aging will be considered. Advances in understanding the molecular regulation of Ca(2+) homeostasis and how it is perturbed in neurological disorders may lead to therapeutic strategies that modulate neuronal Ca(2+) signaling to enhance function and counteract disease processes.