GSK-3 (EC 2.7.11.26), originally identified in 1980, is one of the few signaling mediators that play central roles in a diverse range of signaling pathways, including those activated by Wnts, hedgehog, growth factors, cytokines, and G protein-coupled ligands. It has been implemented in the mechanisms that regulate cellular proliferation, migration, inflammation and immune responses, glucose regulation, and apoptosis. For example: active GSK-3 suppresses pro-proliferation substrates, such as β-catenin, Myc, Jun and Snail, and enhances pro-differentiation substrates, such as p53, Rb, PTEN and TSC1/2. Although the original name suggests the enzyme is involved only in the process of glycogen metabolism, recent findings have revealed over 50 substrates that are phosphorylated by GSK-3, among them the microtubule-associated protein, tau, that is the predominant component of neurofibrillary tangles in Alzheimer’s disease. Despite the impressive number of processes the enzyme is involved in, only four key mechanisms have been identified that contribute to regulating the actions of GSK3 in a substrate-specific manner. The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway activated in response to insulin and many other growth factors often is a major regulator of GSK3 because Akt phosphorylates GSK3 on these inhibitory serine residues, but several other kinases also can phosphorylate these regulatory serines, such as protein kinase C and protein kinase A.Recently, researchers found that inhibition of GSK-3 activity desensitizes cells to mTOR inhibitors but sensitizes cells to PLK1 inhibitors. In line with this observation, it has been hypothesized that GSK-3 inhibitors could be used to enhance the efficacy of PLK1 inhibitors, for example. Additionally, if GSK-3 activity were increased or reactivated by a targeted small molecule, cells would become resensitized to drugs from diverse drug classes, from nucleotide analogs to tyrosine kinase inhibitors.