Recombinant aequorin has been extensively used in mammalian and plant systems as a powerful tool for calcium monitoring. While aequorin has also been widely applied in yeast research, a notable gap exists in the literature regarding comprehensive reviews of these applications. This review aims to address that gap by providing an overview of how aequorin has been used to explore calcium homeostasis, signaling pathways, and responses to stressors, heavy metals, and toxic compounds in . We also discuss strategies for further developing the aequorin system in yeast, with particular emphasis on its use as a model for human calcium signaling studies, such as the reproduction of the mitochondrial calcium uniporter. By highlighting previous research and pinpointing potential future applications, we discuss the untapped potential of aequorin in yeast for drug screening, environmental toxicity testing, and disease-related studies.