The article reviews the history and significance of calcium (Ca²⁺) signaling, tracing its development from a serendipitous discovery in 1883 to its current status as a critical regulator of cellular processes. Initially, Sidney Ringer's experiment with isolated rat hearts revealed that Ca²⁺ was essential for heart contraction, marking the beginning of Ca²⁺ signaling research. However, this discovery did not immediately attract widespread attention. It was not until the 1950s that seminal discoveries, such as the binding of Ca²⁺ to myofibrils and the accumulation of Ca²⁺ in sarcoplasmic reticulum vesicles, began to build a solid foundation for the understanding of Ca²⁺ signaling. The article highlights the contributions of pioneers like L. V. Heilbrunn and K. Bailey, who provided compelling evidence for the role of Ca²⁺ as a messenger. The rapid advancement of Ca²⁺ research has led to a vast literature, but the article focuses on significant recent advances. It discusses the role of Ca²⁺ binding proteins, such as EF hand proteins, in decoding Ca²⁺ signals and their importance in various cellular processes. The crystal structure of the SERCA pump, a key enzyme in Ca²⁺ transport, has provided crucial insights into its mechanism. The article also explores the dynamics of Ca²⁺ waves and oscillations, which are essential for efficient signal transmission and regulation of cellular processes. The text further delves into the versatility of Ca²⁺ signaling, its role in gene expression, and its involvement in memory formation. It highlights the importance of Ca²⁺ in processes like long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus, where Ca²⁺-dependent proteins like CaMKII play a central role. The article concludes by discussing the pathological consequences of abnormal Ca²⁺ signaling, including diseases related to Ca²⁺ pump and receptor defects, and the impact of Ca²⁺ on muscle disorders and hearing loss. Overall, the article underscores the profound impact of Ca²⁺ signaling on cellular function and the ongoing efforts to understand and manipulate this critical process.The article reviews the history and significance of calcium (Ca²⁺) signaling, tracing its development from a serendipitous discovery in 1883 to its current status as a critical regulator of cellular processes. Initially, Sidney Ringer's experiment with isolated rat hearts revealed that Ca²⁺ was essential for heart contraction, marking the beginning of Ca²⁺ signaling research. However, this discovery did not immediately attract widespread attention. It was not until the 1950s that seminal discoveries, such as the binding of Ca²⁺ to myofibrils and the accumulation of Ca²⁺ in sarcoplasmic reticulum vesicles, began to build a solid foundation for the understanding of Ca²⁺ signaling. The article highlights the contributions of pioneers like L. V. Heilbrunn and K. Bailey, who provided compelling evidence for the role of Ca²⁺ as a messenger. The rapid advancement of Ca²⁺ research has led to a vast literature, but the article focuses on significant recent advances. It discusses the role of Ca²⁺ binding proteins, such as EF hand proteins, in decoding Ca²⁺ signals and their importance in various cellular processes. The crystal structure of the SERCA pump, a key enzyme in Ca²⁺ transport, has provided crucial insights into its mechanism. The article also explores the dynamics of Ca²⁺ waves and oscillations, which are essential for efficient signal transmission and regulation of cellular processes. The text further delves into the versatility of Ca²⁺ signaling, its role in gene expression, and its involvement in memory formation. It highlights the importance of Ca²⁺ in processes like long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus, where Ca²⁺-dependent proteins like CaMKII play a central role. The article concludes by discussing the pathological consequences of abnormal Ca²⁺ signaling, including diseases related to Ca²⁺ pump and receptor defects, and the impact of Ca²⁺ on muscle disorders and hearing loss. Overall, the article underscores the profound impact of Ca²⁺ signaling on cellular function and the ongoing efforts to understand and manipulate this critical process.