A rise in cytosolic calcium concentration ([Ca2+]cyt) is central to platelet activation. Agonists stimulate a rise in [Ca2+]cyt through a combination of Ca2+ release from intracellular stores located in the dense tubular system (DTS) and acidic organelles as well as Ca2+ entry across the plasma membrane via several channel types. [Ca2+]cyt may be reduced by Ca2+ sequestration into the intracellular stores by sarco-endoplasmic reticulum Ca2+-ATPases (SERCAs) and via an H+-dependent mechanism, whilst Ca2+ is removed across the plasma membrane by plasma membrane Ca2+-ATPases (PMCAs) and by Na+/Ca2+ exchangers (NCXs). Ca2+ signals are shaped by differential employment of these basic Ca2+ entry and removal processes and by Ca2+ buffers present in the platelet cytosol and other cellular compartments. In turn, Ca2+ signals can be transduced into multiple platelet responses by an array of effector proteins that may be activated in some cases by Ca2+ signals confined to specific cellular microdomains.