This review article explores the mutual interplay between calcium and reactive oxygen species (ROS) in cellular signaling. Calcium, an essential second messenger, plays a crucial role in various cellular processes, including contraction, secretion, metabolism, gene expression, and cell survival. ROS, initially considered detrimental byproducts of aerobic metabolism, are now recognized as signaling molecules involved in growth and cell death. The article discusses how calcium and ROS interact, with calcium regulating ROS formation and ROS modulating calcium signaling. It highlights the importance of this crosstalk in cardiovascular diseases, neurodegenerative disorders, inflammatory diseases, and cancer. The review also examines the specific roles of mitochondria, NADPH oxidases, and the endoplasmic reticulum in this interplay, emphasizing the bidirectional communication between calcium and ROS. Finally, it concludes by suggesting that understanding the mechanisms underlying the interplay between calcium and ROS could lead to novel therapeutic strategies for various diseases.This review article explores the mutual interplay between calcium and reactive oxygen species (ROS) in cellular signaling. Calcium, an essential second messenger, plays a crucial role in various cellular processes, including contraction, secretion, metabolism, gene expression, and cell survival. ROS, initially considered detrimental byproducts of aerobic metabolism, are now recognized as signaling molecules involved in growth and cell death. The article discusses how calcium and ROS interact, with calcium regulating ROS formation and ROS modulating calcium signaling. It highlights the importance of this crosstalk in cardiovascular diseases, neurodegenerative disorders, inflammatory diseases, and cancer. The review also examines the specific roles of mitochondria, NADPH oxidases, and the endoplasmic reticulum in this interplay, emphasizing the bidirectional communication between calcium and ROS. Finally, it concludes by suggesting that understanding the mechanisms underlying the interplay between calcium and ROS could lead to novel therapeutic strategies for various diseases.