Calcium ions are crucial messengers in the regulation of synaptic efficacy. In the postsynaptic neuron, this is exemplified by the tight temporal and spatial co-segregation of calcium ions with calcium-dependent signal transduction protein complexes in dendritic spines. Over the last several years optical imaging, physiological, structural, and biological studies have clarified the molecular mechanisms underlying differential calcium signaling within the spine. In this review, we discuss how calcium signaling "microdomains" are organized and regulated. We emphasize the structural and functional features of precisely regulated supramolecular complexes incorporating proteins involved in calcium influx, calcium efflux, and signal transduction. These complexes act in concert to orchestrate the sophisticated postsynaptic calcium signaling that underlies synaptic plasticity.