Abstract: Aberrant activation of Signal Transducers and Activators of Transcription (STATs), a family of transcription factors, has been associated with a variety of cancers. STATs lie at the conjunction of many different signaling pathways and thus present an attractive target for chemotherapeutic intervention. Among signals which lead to STAT activation, interleukin 6 (IL-6), is of particular interest, as it is part of a family of cytokines which have broad actions on epithelial, hematopoietic, and neuronal cells. A recent report indicated that while both IL-6 and the IL-6 receptor are expressed to a small extent on normal colonic epithelium, both are expressed to a much greater degree in colonic carcinomas. We find that IL-6 activates STAT1 in colorectal carcinoma cells and this activation is sufficient to render the cells resistant to apoptotic signals. Because failure to respond to apoptotic signals is a feature of colon cancer development, we tested the hypothesis that certain compounds achieve their chemoprotective effect through inhibition of this pathway. We demonstrate that bioactive compound butyrate inhibits IL-6 mediated STAT1 activation through down regulation of the IL-6 receptor. While butyrate does not appear to effect the cellular growth and survival, it is sufficient to resensitize cells to apoptotic signals. Non-steroidal anti inflammatory drug (NSAID) consumption has been associated with a marked reduction in risk for developing colon cancer. We found that NSAIDs inhibited STAT activation in cells lines derived from cancerous colon tissue. However, loss of STAT1 expression was not sufficient to recapitulate the protective effect of NSAIDs in a mouse model of colon cancer. While it is clear that they inhibit STAT1 activation, these results suggest that NSAIDs prevent polyp formation through signaling pathways distinct from STAT1 signaling. In order to better understand the mechanisms underlying the aberrant activation of STATs, we studied the effects of various gain-of-function STAT mutants. Using these constructs we were able to observe novel basal phosphorylation of STATs 1 and 3. We find that the cysteine residues in disulfide containing constitutively active STAT mutants stabilize STAT tyrosine phosphorylation and interaction with DNA. This stabilization preserves previously undetected basal phosphorylation, resulting in a build-up of activated STATs. The data presented in this dissertation suggest that IL-6 mediated STAT1 activation is an attractive target for chemotherapeutic intervention. Furthermore, the presence of previously undescribed basal phosphorylation of STATs suggests that lesions in dephosphorylation may be the underlying cause of aberrant STAT activation in other cancers.