Abstract Calcium (Ca2+) is an essential nutrient for plants. It is a counter-cation for organic and inorganic anions in the vacuole, which is crucial for different structural functions in the cell wall and membranes. Besides, it coordinates responses to an array of developmental and environmental challenges. Its uptake involves its entry from soil solution into root cells through Ca2+-specific ion channels followed by entry into shoot cells, and this process is influenced by metabolism and temperature. Phytohormones, rootstock, and genotype also control the uptake and transportation of Ca2+. Therefore, the biology of uptake and translocation of Ca2+ is very complex. The present book chapter highlights the current knowledge of the intricate mechanism of Ca2+ uptake and translocation decoded by systems biology approaches in some model plants i.e., Arabidopsis thaliana, Oryza sativa, few millet crops, and so on and available information in the scientific literature. Besides, it also provides the role of key components such as calcium exchangers/transporters/sensors, and so on and their importance in whole plant systems. This updated information, which is demonstrated in the present chapter, will be highly useful for scientific readers for understanding the systems biology of Ca2+ uptake and translocation.