Recent studies have uncovered that one of the critical signaling molecules that is involved in human breast cancer progression is the STAT-3 transcription factor. Work in the past few years from our group has established that epithelial disruption of STAT-3 in a doxycycline inducible PyV mT transgenic mouse model of breast cancer results in a profound block in mammary tumour induction. Molecular and pathological analyses of tumor progression revealed that STAT3 deficient tumours were initially able to form hyperplastic and early adenoma–like lesions with no obvious impact on the proliferative or apoptotic status on these epithelial lesions. However, these early premalignant lesions completely regressed, thereby preventing the emergence of mammary tumours in the majority of animals. This further correlated with the infiltration of CD3 positive T lymphocytes and F4/80 positive macrophages into STAT3 deficient lesions, prior to regression. Based on preliminary data, we hypothesize that mammary epithelial expression of STAT3 plays a critical role in inducing an immunosuppressive tumour microenvironment and its disruption results in a rapid induction of an anti-tumor immune response. However, focal mammary tumours eventually rise in 40% of female mice after a long latency period. By contrast to the early pre-malignant lesions that possess immune infiltrates, these later tumours lack evidence of infiltrating immune cells indicating that they have broken immune surveillance. Molecular and biochemical analyses of these tumors revealed that they failed to metastasize due to lack of a pro-inflammatory gene expression profile. These observations indicate that STAT3 plays a critical role in modulating the tumour immune microenvironment.