Glycogen synthase kinase-3beta (GSK-3beta), a serine/threonine protein kinase, is a complex regulator of numerous cellular functions. GSK-3beta is a unique kinase which is constitutively active in resting and nonstimulated cells. GSK-3beta has been implicated in a wide range of diseases including neurodegeneration, inflammation and fibrosis, noninsulin-dependent diabetes mellitus, and cancer. It is a regulator of NF-kappaB-mediated survival of cancer cells, which provided a rationale for the development of GSK-3 inhibitors targeting malignant tumors. Recent studies, many of them reported over the past decade, have identified GSK-3beta as a potential therapeutic target in more than 15 different types of cancer. Whereas only active GSK-3beta is expressed in cancer cell nucleus, aberrant nuclear accumulation of GSK-3beta has been identified as a hallmark of cancer cells in malignant tumors of different origin. This review focuses on the preclinical and clinical development of GSK-3 inhibitors and the potential therapeutic impact of targeting GSK-3beta in human cancer. Clin Cancer Res; 23(8); 1891-7. (c)2017 AACR.