Abstract: Calcineurin (CN) is a calcium- and calmodulin-dependent serine/threonine that has been studied in many model organisms including yeast, filamentous fungi, plants, and mammals. Its biological functions range from ion homeostasis and virulence in lower eukaryotes to T-cell activation in humans by human nuclear factors of activated T-cells. CN is a heterodimeric protein consisting of a catalytic subunit, calcineurin A (Cna1p), which contains an active site with a dinuclear metal center, and a regulatory Ca2+ binding subunit called calcineurin B (Cnb1p) required to activate Cna1p. The calcineurin B subunit has been highly conserved through evolution: For example, the mammalian calcineurin B shows 54% identity with calcineurin B from Saccharomyces cerevisiae. Notably, CN regulates post-translational modifications of target proteins and gene expression in parallel. The substrate selection for CN includes, but is not limited to, transcription factors, ion pumps/channels, proteins associated with mitochondria, vesicle trafficking and the polarity machinery through interactions with microtubules. The docking sites such as Short linear motifs or LxVP drive CN’s dynamic interaction and selection of its targets. The CN substrate networks in yeast and animals are distinct but share a common repertoire of target kinases, such as PKA, PKC, AKT, CAMKL, and proline-directed GSK3, CDK, and MAPK kinases. Rcn1p/RCAN1p, which regulates and activates CN in a feedback loop–dependent manner during Ca2+ stress, is the only CN target known to be conserved in yeast and mammals (Creamer, 2020). Interestingly, altered RCAN1 expression is associated with Down’s syndrome whereas its elevated expression is associated with the onset of neuronal Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease (PD) pathology in human patients.