Non-cancerous stromal cells in the tumor microenvironment, such as cancer-associated fibroblasts (CAFs), support tumor growth and malignancy and must undergo changes in gene expression to do so. A new study by Susan Lindquist, Luke Whitesell and colleagues identifies activated heat shock protein HSF1 as a key player in this transcriptional reprogramming (Cell 158, 564–578, 2014). The authors found that HSF1 localized to the nucleus in CAFs from breast cancer samples, indicating that it was active, in contrast to the predominately cytoplasmic (inactive) HSF1 in fibroblasts from normal breast tissue. Following co-culture experiments of wild-type and Hsf1-deficient mouse embryonic fibroblasts (MEFs) and D2A1 cancer cells, expression array analysis showed that 219 genes were specifically upregulated in cancer cells grown in the presence of MEFs expressing HSF1. This gene set was enriched for genes with roles in extracellular matrix (ECM) formation and cell adhesion, whereas genes involved in cytokine signaling and immune response were downregulated. Cancer cells similarly affected the transcriptome of co-cultured wild-type but not Hsf1-null MEFs, upregulating genes related to cell proliferation and wound response. The authors found that HSF1 exerts these effects through the TGF-β and SDF1 signaling pathways. Finally, they showed that activation of HSF1 in tumor stromal cells from patients with breast and lung cancer was correlated with poor clinical outcome.