Calcium and reactive oxygen species (ROS) are interdependent signaling molecules that regulate a wide range of cellular processes, including cell survival, death, and signaling pathways. Calcium ions (Ca²⁺) are crucial for intracellular signaling and are involved in various cellular functions such as contraction, secretion, and gene expression. ROS, initially considered harmful byproducts of aerobic metabolism, are now recognized as signaling molecules that play essential roles in cellular processes, including growth and cell death. The interplay between calcium and ROS signaling is complex and bidirectional, with each influencing the other. Dysregulation in either system can lead to harmful effects, contributing to the pathogenesis of various disorders. Calcium signaling pathways interact with ROS pathways, and both systems are regulated by various mechanisms. For example, calcium can influence ROS generation through mitochondrial and NADPH oxidase pathways, while ROS can modulate calcium homeostasis by affecting calcium channels, pumps, and exchangers. Mitochondrial ROS and calcium are particularly important, as mitochondrial calcium uptake is crucial for energy production and cellular physiology. However, excessive mitochondrial calcium can lead to cell death pathways such as apoptosis and necrosis. ROS are generated through various sources, including mitochondrial respiratory chain activity and extramitochondrial enzymes such as NADPH oxidases. ROS can also be generated by calcium-dependent pathways, and both calcium and ROS can influence each other's signaling. The interaction between calcium and ROS is highly dependent on the cell and tissue type, and it has been studied mainly in the cardiovascular system, where they converge at dyads, the structural and functional units of cardiac excitation-contraction coupling. The interplay between calcium and ROS is also important in other systems, including neurodegenerative diseases such as Parkinson's and Alzheimer's, inflammatory diseases, and cancer. The review discusses the cross-talk between calcium and ROS, with a focus on mitochondria, the important extramitochondrial ROS source NADPH oxidase, and their interaction with the endoplasmic reticulum. The review highlights the importance of understanding the calcium-ROS interplay in various physiological and pathological conditions.Calcium and reactive oxygen species (ROS) are interdependent signaling molecules that regulate a wide range of cellular processes, including cell survival, death, and signaling pathways. Calcium ions (Ca²⁺) are crucial for intracellular signaling and are involved in various cellular functions such as contraction, secretion, and gene expression. ROS, initially considered harmful byproducts of aerobic metabolism, are now recognized as signaling molecules that play essential roles in cellular processes, including growth and cell death. The interplay between calcium and ROS signaling is complex and bidirectional, with each influencing the other. Dysregulation in either system can lead to harmful effects, contributing to the pathogenesis of various disorders. Calcium signaling pathways interact with ROS pathways, and both systems are regulated by various mechanisms. For example, calcium can influence ROS generation through mitochondrial and NADPH oxidase pathways, while ROS can modulate calcium homeostasis by affecting calcium channels, pumps, and exchangers. Mitochondrial ROS and calcium are particularly important, as mitochondrial calcium uptake is crucial for energy production and cellular physiology. However, excessive mitochondrial calcium can lead to cell death pathways such as apoptosis and necrosis. ROS are generated through various sources, including mitochondrial respiratory chain activity and extramitochondrial enzymes such as NADPH oxidases. ROS can also be generated by calcium-dependent pathways, and both calcium and ROS can influence each other's signaling. The interaction between calcium and ROS is highly dependent on the cell and tissue type, and it has been studied mainly in the cardiovascular system, where they converge at dyads, the structural and functional units of cardiac excitation-contraction coupling. The interplay between calcium and ROS is also important in other systems, including neurodegenerative diseases such as Parkinson's and Alzheimer's, inflammatory diseases, and cancer. The review discusses the cross-talk between calcium and ROS, with a focus on mitochondria, the important extramitochondrial ROS source NADPH oxidase, and their interaction with the endoplasmic reticulum. The review highlights the importance of understanding the calcium-ROS interplay in various physiological and pathological conditions.