Ca2+ ions passing through a single or a cluster of Ca2+-permeable channels create microscopic, short-lived Ca2+ gradients that constitute the building blocks of cellular Ca2+ signaling. Over the last decade, imaging microdomain Ca2+ in muscle cells has unveiled the exquisite spatial and temporal architecture of intracellular Ca2+ dynamics and has reshaped our understanding of Ca2+ signaling mechanisms. Major advances include the visualization of "Ca2+ sparks" as the elementary events of Ca2+ release from the sarcoplasmic reticulum (SR), "Ca2+ sparklets" produced by openings of single Ca2+-permeable channels, miniature Ca2+ transients in single mitochondria ("marks"), and SR luminal Ca2+ depletion transients ("scraps"). As a model system, a cardiac myocyte contains a 3-dimensional grid of 104 spark ignition sites, stochastic activation of which summates into global Ca2+ transients. Tracking intermolecular coupling between single L-type Ca2+ channels and Ca2+ sparks has provided direct evidence validating the local control theory of Ca2+-induced Ca2+ release in the heart. In vascular smooth muscle myocytes, Ca2+ can paradoxically signal both vessel constriction (by global Ca2+ transients) and relaxation (by subsurface Ca2+ sparks). These findings shed new light on the origin of Ca2+ signaling efficiency, specificity, and versatility. In addition, microdomain Ca2+ imaging offers a novel modality that complements electrophysiological approaches in characterizing Ca2+ channels in intact cells.