Intracellular Ca2+ is regulated within three major compartments: the cytosol, the endoplasmic reticulum and mitochondria. This Chapter reviews the mechanisms involved in handling of Ca2+ within these compartments with reference to potential strategies for neuroprotection. In the cytosol, Ca2+ buffering has a major influence on Ca2+ signals. Cytosolic Ca(2+)-binding proteins such as CB28 participate in Ca2+ buffering and may have a role in resistance to neurotoxicity. In the endoplasmic reticulum, a number of proteins are involved in Ca2+ uptake, lumenal buffering or release, and these may be of value as potential targets for therapeutic intervention. Mitochondria are receiving increasing attention for their role in Ca2+ storage and signaling, and as key players in the processes leading to cell death following Ca2+ overload. An improved understanding of how Ca2+ is controlled within these intracellular compartments, and how these compartments interact, will be important for neuroprotective strategies.