Stat3 was independently discovered and studied by two research groups and described in 1994. Akira et al. purified and cloned Stat3 from mouse liver nuclear extracts, named it as acute-phase response factor (APRF), and also identified Stat3 as a DNA-binding factor that selectively binds to the IL-6-responsive element within the acute-phase gene promoter. 3 Zhong et al. discovered Stat3 as a DNA-binding protein in response to epidermal growth factor. 4 Since then, multiple Stat3 isoforms have been identified, including the long form Stat3α, the truncated forms Stat3β and Stat3γ, and a putative novel form Stat3δ, 5 all derived from a single gene located within chromosome 17q21 via alternative splicing of the transcript’s 3′ end. 5 Stat3α (p92), a 770 amino acid protein, is the predominantly expressed form of Stat3 in most cell types. 6 Stat3β (p83) is an alternatively spliced RNA form of Stat3α, in which the 55 C-terminal amino acids of the transactivation domain are replaced by seven distinct amino acids. Stat3β was generally regarded as a dominant negative Stat3 isoform 7 until recent in vivo experimental evidence showed that Stat3β rescued the embryonic lethality of a Stat3-null mutation and was capable by itself of activating the expression of Stat3 target genes. 8 Compared with Stat3α and Stat3β, the physiologic roles of Stat3γ and Stat3δ are less clear. Stat3γ (p72) is another C-terminal truncated form of Stat3α derived post-translationally through limited proteolysis. Stat3γ is primarily activated in terminally differentiated neutrophils. 9 Stat3δ exists at low levels and decreases with cell differentiation. 5 In this review, we summarize the signaling pathways of Stat3, its role in different diseases as well as in stem cell maintenance, and the progress in the design, discovery, and development of Stat3 inhibitors since 2006.