Research in recent years has accumulated a wealth of novel insight into mechanisms by which tumor cells interact with activated fibroblasts, endothelial cells, inflammatory and immune cells and the extracellular matrix. Cancer and stromal cells co-evolve throughout tumorigenesis. As a result, the tumor stroma is now regarded as an essential contributor to tumor establishment, progression and dissemination. Moreover, the formation of suitable stroma niches has emerged as a prime determinant of metastasis. Notably, malignant tumors adopt numerous mechanisms that are also operative in embryonic and adult stem cell biology. Tumor sites show functional characteristics with striking similarities to stem cell niches. This review summarizes the current view of disease-relevant communication between tumor cells and the tumor stroma and relates it to interactions of stem cells and their respective niches. Progress in understanding the pivotal role of the microenvironment in both tumor and stem cell biology renders the tumor stroma an interesting potential future target for specific cancer therapies.