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Most signaling pathways cause activation of their components in response to changes in a cell's environment. However, a highly conserved protein kinase termed GSK-3 does quite the opposite, and this may be one of the reasons its function is regulated by multiple signaling systems. GSK-3 is inhibited in response to the Wnt, phosphatidylinositol, and adenosine 3′-5′-monophosphate (cAMP) pathways. A convergence of studies of this enzyme using a variety of organisms from yeast to mouse is revealing the molecular mechanisms by which GSK-3 selectively responds to these signals, along with providing clues to its biological functions. Important insights are being made into the importance of organization of signaling proteins in dictating their specificity. Given its relevance to a number of human diseases, including cancer and neurological disorders, such information may lead to selective therapeutic antagonists of the enzyme.