Glycogen synthase kinase-3 (GSK3) is a highly regulated kinase with over 100 known substrates, playing a critical role in various cellular signaling pathways and numerous diseases. This review discusses the regulation, actions, and disease involvement of GSK3, emphasizing its adaptability and the mechanisms that allow it to selectively phosphorylate substrates. GSK3 is regulated through post-translational modifications, substrate priming, cellular trafficking, and protein complexes. Key regulatory mechanisms include inhibitory serine-phosphorylation, which controls GSK3 activity by modulating its interaction with substrates. GSK3's ability to phosphorylate substrates is influenced by their pre-phosphorylation status, subcellular localization, and association with protein complexes. GSK3 is involved in multiple diseases, including Alzheimer's disease, depression, cancer, and inflammatory conditions. Its involvement in these diseases highlights the potential of GSK3 as a therapeutic target. Recent studies have shown that GSK3 can interact with various receptors and signaling pathways, including G protein-coupled receptors and hormone receptors, further expanding its role in cellular regulation. The review also discusses the differential actions of GSK3 isoforms, GSK3α and GSK3β, and the importance of understanding their regulatory mechanisms for developing targeted therapies. Overall, GSK3's complex regulatory mechanisms and wide-ranging biological functions make it a key player in cellular signaling and disease processes.Glycogen synthase kinase-3 (GSK3) is a highly regulated kinase with over 100 known substrates, playing a critical role in various cellular signaling pathways and numerous diseases. This review discusses the regulation, actions, and disease involvement of GSK3, emphasizing its adaptability and the mechanisms that allow it to selectively phosphorylate substrates. GSK3 is regulated through post-translational modifications, substrate priming, cellular trafficking, and protein complexes. Key regulatory mechanisms include inhibitory serine-phosphorylation, which controls GSK3 activity by modulating its interaction with substrates. GSK3's ability to phosphorylate substrates is influenced by their pre-phosphorylation status, subcellular localization, and association with protein complexes. GSK3 is involved in multiple diseases, including Alzheimer's disease, depression, cancer, and inflammatory conditions. Its involvement in these diseases highlights the potential of GSK3 as a therapeutic target. Recent studies have shown that GSK3 can interact with various receptors and signaling pathways, including G protein-coupled receptors and hormone receptors, further expanding its role in cellular regulation. The review also discusses the differential actions of GSK3 isoforms, GSK3α and GSK3β, and the importance of understanding their regulatory mechanisms for developing targeted therapies. Overall, GSK3's complex regulatory mechanisms and wide-ranging biological functions make it a key player in cellular signaling and disease processes.