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As knowledge of cellular signal transduction has accumulated, general truisms have emerged, including the notion that signaling proteins are usually activated by stimuli and that they, in turn, mediate the actions of specific agonists. Glycogen synthase kinase-3 (GSK-3) is an unusual protein-serine kinase that bucks these conventions. This evolutionarily conserved protein kinase is active in resting cells and is inhibited in response to activation of several distinct pathways, including those acting by elevation of 3′ phosphorylated phosphatidylinositol lipids and adenosine 3′-5′-monophosphate (cAMP). In addition, GSK-3 is distinctly regulated by, and is a core component of, the Wnt pathway. This review describes the unique characteristics of this decidedly oddball protein kinase in terms of its diverse biological functions, plethora of targets, role in several human diseases, and consequential potential as a therapeutic target.