Chronic inflammation is a contributing factor to overall cancer risk as well as cancer promotion and progression; however, pathways regulating onset of cancer-promoting inflammatory responses are still poorly understood. Clinical data suggest that deficient anti-tumor cell-mediated immunity, in combination with enhanced pro-tumor humoral and/or innate immunity (inflammation), are significant factors influencing malignant outcome. Here, we discuss therapeutic implications from clinical data and experimental studies using de novo immune-competent mouse models of cancer development that together are revealing molecular and cellular mechanisms underlying interactions between immune cells and evolving neoplastic cells that regulate cancer outcome. Understanding the functionally significant links between adaptive and innate immunity that regulate cancer development will open new therapeutic opportunities to manipulate aspects of immunobiology and minimize lethal effects of cancer development. J. Cell. Biochem. 101: 918–926, 2007. © 2007 Wiley-Liss, Inc.