Stat3 in different cells (5). For instance, part of the mechanism by which Stat3 stimulates B cell proliferation is through inhibition of apoptosis, a function mediated by induction of the antiapoptotic gene Bcl-2. In contrast, activation of Stat3 in monocytic cells leads to downregulation of c-myc and c-myb and induction of junB and IRF-1, a pattern of gene regulation consistent with differentiation and growth arrest. Likewise, a different set of Stat3-dependent genes are upregulated in IL-6–stimulated hepatocytes, genes for the secreted proteins of the acute-phase response (20). Additional signaling systems also appear to rely heavily on Stat3, at least in cell culture systems. For instance, G-CSF receptor signaling during granulopoiesis leads to a striking activation of Stat3. Moreover, the Stat3 requirement site on the receptor is required for G-CSF–driven proliferation, and expression of dominant negative Stat3 impairs proliferation (21). HGF activates Stat3 during the process of tubule outgrowth in epithelial cells (22). IL-10 requires Stat3 activation for its anti-inflammatory properties on macrophages (23). How a common transcription factor activates a distinct gene program dependent on cell type is an area of active investigation. Stat3, like other Stat proteins (24), has also been implicated in cancer (see Bromberg, this Perspective series, ref. 25; and references therein). Following the seminal discovery that Stat3 is constitutively phosphorylated in v-Src–transformed cells (26), considerable evidence has accumulated suggesting a critical role for activated Stat3 during malignant transformation. Activated Stat3 has been observed in a variety of experimental malignancies, and its abrogation by use of dominant negative inhibitors or antisense oligonucleotides has led to reversal of the malignant phenotype. Expression of a constitutively active version of Stat3 on its own can lead to fibroblast transformation, suggesting that Stat3 is an oncogene. Moreover, numerous mouse and human malignancies have shown activated Stat3, including many head and neck cancers, mammary carcinomas, multiple myelomas, and other hematological malignancies. In these situations, Stat3 has been described as mediating largely a survival function, and induction of such antiapoptotic genes as Bcl-2 and Bcl-X has been suggested as a target of Stat3 action.