Stromal cells within the tumor microenvironment are essential for tumor progression and metastasis. Surprisingly little is known about the factors that drive the transcriptional reprogramming of stromal cells within tumors. We report that the transcriptional regulator heat shock factor 1 (HSF1) is frequently activated in cancer-associated fibroblasts (CAFs), where it is a potent enabler of malignancy. HSF1 drives a transcriptional program in CAFs that complements, yet is completely different from, the program it drives in adjacent cancer cells. This CAF program is uniquely structured to support malignancy in a non-cell-autonomous way. Two central stromal signaling molecules—TGF-β and SDF1—play a critical role. In early-stage breast and lung cancer, high stromal HSF1 activation is strongly associated with poor patient outcome. Thus, tumors co-opt the ancient survival functions of HSF1 to orchestrate malignancy in both cell-autonomous and non-cell-autonomous ways, with far-reaching therapeutic implications. Display omitted •Reprogramming of cancer-associated fibroblasts by HSF1 enables malignant progression•Distinct transcriptional programs are driven by HSF1 in stromal versus malignant cells•HSF1 activation in tumor stroma is strongly associated with poor patient outcome•Dual roles in both tumor cells and stroma make HSF1 an attractive anticancer target HSF1 drives a transcriptional program in stromal cells that potentiates tumor cell malignancy and is associated with poor patient outcomes.