Calcium signals mediate diverse cellular functions in immunological cells. Early studies with mast cells, then a preeminent model for studying Ca2+-dependent exocytosis, revealed several basic features of calcium signaling in non-electrically excitable cells. Subsequent studies in these and other cells further defined the basic processes such as inositol 1,4,5-trisphosphate-mediated release of Ca2+ from Ca2+ stores in the endoplasmic reticulum (ER); coupling of ER store depletion to influx of external Ca2+ through a calcium-release activated calcium (CRAC) channel now attributed to the interaction of the ER Ca2+ sensor, stromal interacting molecule-1 (STIM1), with a unique Ca2+-channel protein, Orai1/CRACM1, and subsequent uptake of excess Ca2+ into ER and mitochondria through ATP-dependent Ca2+ pumps. In addition, transient receptor potential channels and ion exchangers also contribute to the generation of calcium signals that may be global or have dynamic (e.g., waves and oscillations) and spatial resolution for specific functional readouts. This review discusses past and recent developments in this field of research, the pharmacologic agents that have assisted in these endeavors, and the mast cell as an exemplar for sorting out how calcium signals may regulate multiple outputs in a single cell.