Ten years ago, Hanahan and Weinberg delineated six “Hallmarks of cancer” which summarize several decades of intense cancer research. However, tumor cells do not act in isolation, but rather subsist in a rich microenvironment provided by resident fibroblasts, endothelial cells, pericytes, leukocytes, and extra-cellular matrix. It is increasingly appreciated that the tumor stroma is an integral part of cancer initiation, growth and progression. The stromal elements of tumors hold prognostic, as well as response-predictive, information, and abundant targeting opportunities within the tumor microenvironment are continually identified. Herein we review the current understanding of tumor cell interactions with the tumor stroma with a particular focus on cancer-associated fibroblasts and pericytes. Moreover, we discuss emerging fields of research which need to be further explored in order to fulfil the promise of stroma-targeted therapies for cancer.