In eukaryotic cells, a rise in cytoplasmic Ca²⁺ can activate a plethora of responses that operate on time scales ranging from milliseconds to days. Inherent to the use of a promiscuous signal like Ca²⁺ is the problem of specificity: how can Ca²⁺ activate some responses but not others? We now know that the spatial profile of the Ca²⁺ signal is key. Ca²⁺ does not simply rise uniformly throughout the cytoplasm upon stimulation but can reach very high levels locally, creating spatial gradients. The most fundamental local Ca²⁺ signal is the Ca²⁺ microdomain that develops rapidly near open plasmalemmal Ca²⁺ channels like voltage-gated L-type (Cav1.2) and store-operated CRAC channels. Recent work has revealed that Ca²⁺ microdomains arising from these channels are remarkably versatile in triggering a range of responses that differ enormously in both temporal and spatial profile. Here, I delineate basic features of Ca²⁺ microdomains and then describe how these highly local signals are used by Ca²⁺-permeable channels to drive cellular responses.