STATs comprise a family of transcription factors that mediate intracellular signaling usually generated at cell surface receptors and transmitted to the nucleus.Several studies have demonstrated aberrant activation of pro-inflammatory transcription factor STAT3 in a wide variety of human tumors, including hematological malignancies (leukemias,lymphomas, and multiple myeloma) as well as solid tumors (such as head and neck, breast, lung, gastric, hepatocellular,and prostate cancers).There is a strong evidence to suggest that constitutive STAT3 signaling promotes cancer development and progression by either inhibiting apoptosis or inducing cell proliferation, inflammation, angiogenesis,invasion, and metastasis.However, the development of pharmacological drugs for targeting STAT3 that are both safe and efficacious remains an important scientific and clinical challenge.We will present recent data from our group that shows that novel small molecule inhibitors (emodin and butein) can suppress STAT3 activation and modulate the expression of genes involved in HCC initiation and progression both in vitro and in vivo.