Glycogen synthase kinase-3 (GSK3) is a highly versatile kinase with over 100 known substrates, playing a crucial role in various cellular processes and diseases. The review discusses the regulatory mechanisms that enable GSK3 to selectively phosphorylate its substrates, including post-translational modifications, substrate priming, cellular trafficking, and protein complexes. GSK3's adaptability is highlighted, particularly its ability to integrate new substrates into its repertoire. The review also covers GSK3's interactions with receptors and receptor-coupled signal transduction events, such as G protein-coupled receptors and hormone receptors, and its differential actions between the two isoforms, GSK3α and GSK3β. Additionally, the therapeutic potential of targeting GSK3 is explored, including its role in treating conditions like Alzheimer's disease, depression, and bipolar disorder. The review emphasizes the complex regulatory mechanisms of GSK3 and its significance in multiple disease processes.Glycogen synthase kinase-3 (GSK3) is a highly versatile kinase with over 100 known substrates, playing a crucial role in various cellular processes and diseases. The review discusses the regulatory mechanisms that enable GSK3 to selectively phosphorylate its substrates, including post-translational modifications, substrate priming, cellular trafficking, and protein complexes. GSK3's adaptability is highlighted, particularly its ability to integrate new substrates into its repertoire. The review also covers GSK3's interactions with receptors and receptor-coupled signal transduction events, such as G protein-coupled receptors and hormone receptors, and its differential actions between the two isoforms, GSK3α and GSK3β. Additionally, the therapeutic potential of targeting GSK3 is explored, including its role in treating conditions like Alzheimer's disease, depression, and bipolar disorder. The review emphasizes the complex regulatory mechanisms of GSK3 and its significance in multiple disease processes.