Colorectal cancer is the 4th most common cancer globally and the 2nd most common cancer in Australia. Constitutive activation of Signal transducer and activator of transcription 3 (STAT3) has been observed in over 50% of human colorectal carcinomas and its role in tumour progression has been confirmed in numerous mouse models. Previous data suggests that signalling through the Epidermal Growth Factor Receptor (EGFR), contributes to STAT3 activation [1]. However, STAT3 activation can also be mediated through the Interleukin (IL)-6 family of cytokines. We hypothesise that STAT3 activation may contribute to resistance to current therapies. In order to better understand how we can overcome these resistance mechanisms, we evaluated the ability of a panel of 1172 FDA approved agents to inhibit both EGF and IL-6 mediated STAT3 activity, monitored by the use of an adenoviral STAT3 luciferase reporter assay, in human colorectal cancer cell lines. We identified over 50 FDA approved agents that inhibited both EGF and IL-6-induced STAT3 activity, including Sunitinib (Sutent), a multi-targeted tyrosine kinase inhibitor currently approved for the treatment of pancreatic neuroendocrine tumors, kidney cancer and gastrointestinal stromal tumors. Additionally, Sunitinib reduced STAT3 phosphorylation and transcriptional activity mediated by IL-11, a closely related IL-6 family member. In each of the examined cell lines, Sunitinib reduced viability suggesting that the reduction in STAT3 activity inhibits cell proliferation. Furthermore, several other multi-targeted tyrosine kinase inhibitors, including Imatinib, Sorafenib and Masitinib also demonstrated STAT3 reduction in each of the cell lines tested. While the effectiveness of Sunitinib either alone or in combination with other anti-cancer agents requires additional investigation, our preliminary findings offer proof-of-principle evidence for the potential use of Sunitinib (and other multi-kinase inhibitors) for the treatment of STAT3 driven colorectal cancers.