Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes, regulating numerous signaling pathways and cellular processes. It is typically constitutively active and regulated through inhibition. GSK-3 preferentially phosphorylates primed substrates, i.e., substrates previously phosphorylated by another kinase. This review covers recent advances in understanding GSK-3 regulation, including the implications of its crystal structure, regulation by serine and tyrosine phosphorylation, roles in the Wnt/β-catenin and Hedgehog pathways, and the development of small molecule inhibitors. GSK-3 is a therapeutic target for diseases such as diabetes, Alzheimer's, and cancer, but its broad range of functions and potential for off-target effects pose challenges.Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase found in all eukaryotes, regulating numerous signaling pathways and cellular processes. It is typically constitutively active and regulated through inhibition. GSK-3 preferentially phosphorylates primed substrates, i.e., substrates previously phosphorylated by another kinase. This review covers recent advances in understanding GSK-3 regulation, including the implications of its crystal structure, regulation by serine and tyrosine phosphorylation, roles in the Wnt/β-catenin and Hedgehog pathways, and the development of small molecule inhibitors. GSK-3 is a therapeutic target for diseases such as diabetes, Alzheimer's, and cancer, but its broad range of functions and potential for off-target effects pose challenges.