In normal adult tissues, paracrine signals that derive from the stem cell niche, or microenvironment, play an important role in regulating the critical balance between activity and quiescence of stem cells. Similarly, evidence has emerged to support the hypothesis that signals derived from the microenvironment regulate cancer cells in an analogous manner. We recently reported that in basal cell carcinoma of the skin and in diverse other solid tumors, fibroblasts that comprise the tumor cell niche are, indeed, molecularly distinct from those that comprise the normal stroma. In particular, we found evidence suggesting that expression of secreted BMP antagonists by tumor-associated stromal cells may promote self-renewal of tumor stem cells in vivo. This chapter describes methods for identifying and evaluating the molecular signals that derive from fibroblasts in human tumors.