Hippocampal synaptic plasticity is widely considered the cellular basis of learning and spatial memory processes. This article highlights the central role of Ca2+ release from the endoplasmic reticulum (ER) in hippocampal synaptic plasticity and hippocampus-dependent memory in health and disease. The key participation of ryanodine receptor (RyR) channels, which are the principal Ca2+ release channels expressed in the hippocampus, in these processes is emphasized. It is proposed that the increased neuronal oxidative tone displayed by hippocampal neurons during aging or Alzheimer's disease (AD) leads to excessive activation of RyR-mediated Ca2+ release, a process that is highly redox-sensitive, and that this abnormal response contributes to and aggravates these deleterious conditions.