Apicomplexan parasites rely on calcium-mediated signaling for a variety of vital functions including protein secretion, motility, cell invasion, and differentiation. These functions are controlled by a variety of specialized systems for uptake and release of calcium, which acts as a second messenger, and on the functions of calcium-dependent proteins. Defining these systems in parasites has been complicated by their evolutionary distance from model organisms and practical concerns in working with small, and somewhat fastidious cells. Comparative genomic analyses of Toxoplasma gondii, Plasmodium spp. and Cryptosporidium spp. reveal several interesting adaptations for calcium-related processes in parasites. Apicomplexans contain several P-type Ca2+ ATPases including an ER-type reuptake mechanism (SERCA), which is the proposed target of artemisinin. All three organisms also contain several genes related to Golgi PMR-like calcium transporters, and a Ca2+/H+ exchanger, while plasma membrane-type (PMCA) Ca2+ ATPases and voltage-dependent calcium channels are exclusively found in T gondii. Pharmacological evidence supports the presence of IP3 and ryanodine channels for calcium-mediated release. Collectively these systems regulate calcium homeostasis and release calcium to act as a signal. Downstream responses are controlled by a family of EF-hand containing calcium binding proteins including calmodulin, and an array of centrin and caltractin-like genes. Most surprising, apicomplexans contain a diversity of calcium-dependent protein kinases (CDPK), which are commonly found in plants. Toxoplasma contains more than 20 CDPK or CDPK-like proteases, while Plasmodium and Cryptosporidium have fewer than half this number. Several of these CDPKs have been shown to play vital roles in protein secretion, invasion, and differentiation, indicating that disruption of calcium-regulated pathways may provide a novel means for selective inhibition of parasites.