Multiple studies have shown that engraftment and subsequent growth rates of human mammary tumor xenografts can be enhanced by coinjection of tumor cells with human fibroblasts or fibroblast-derived soluble factors. It is also apparent that the ability of a given mesenchymal fibroblast to enhance tumor growth is dependent on its tissue of origin (i.e., organ-specificity). However, it is unclear how organ-specific fibroblasts contribute to tumor growth enhancement and how these cells may impact organ-specific metastatic patterning. We examined a panel of primary human mesenchymal fibroblasts to define the extent to which each cell type could impact human breast cancer cell growth and invasion. Two- and three-dimentional in vitro systems in conjunction with in vivo animal models demonstrated that interleukin-6 (IL-6) was a critical factor that promoted human breast cancer cell growth and invasion via downstream STAT3 signaling events. In conjunction with clinical data that link elevated IL-6 to poor clinical outcomes in breast cancer patients, our data suggest that IL-6 may be a critical factor in human breast cancer disease progression. For details, see the article by Studebaker and colleagues on page 9087 of this issue.