The ability to inhibit kinases such as Bcr-Abl, Her2, Flt3, and the epidermal growth factor receptor has ushered in a new generation of targeted therapies, based on the unique molecular abnormalities present in tumor cells. However, activation of most of these kinases is found in only a small fraction of tumors. In most cancers, a variety of kinases may become activated, but the malignant phenotype of a cell is driven through the downstream activation of a relatively small number of transcription factors. One family of transcription factors found to be activated in a wide spectrum of human cancers is the signal transducers and activators of transcription, or STATs. In tumor systems, STAT inhibition has been shown to decrease cellular proliferation and lower the threshold for apoptosis. By contrast, inhibition of STATs in normal tissue is generally well tolerated, presumably due to the presence of complementary or redundant signaling pathways. With increased knowledge regarding the molecular steps in the activation of STATs and other transcription factors, very specific inhibitors can be designed and synthesized. Hence, either alone or in combination with targeted or cytotoxic therapies, inhibition of STATs and other transcription factors may be a powerful new approach towards cancer therapy.