Evidence is accumulating that the malignant phenotype of a given tumor is dependent not only on the intrinsic characteristics of tumor cells, but also on the cooperative interactions of non‐neoplastic cells, soluble secreted factors and the non‐cellular solid‐state ECM network that comprise the tumor microenvironment. Given the ability of the tumor microenvironment to regulate the cellular phenotype, recent efforts have focused on understanding the molecular mechanisms by which cells sense, assimilate, interpret, and ultimately respond to their immediate surroundings. Exciting new studies are beginning to unravel the complex interactions between the numerous cell types and regulatory factors within the tumor microenvironment that function cooperatively to control tumor cell invasion and metastasis. Here, we will focus on studies concerning a common theme, which is the central importance of the non‐cellular solid‐state compartment as a master regulator of the malignant phenotype. We will highlight the non‐cellular solid‐state compartment as a relatively untapped source of therapeutic and imaging targets and how cellular interactions with these targets may regulate tumor metastasis. J. Cell. Physiol. 213: 391–402, 2007. © 2007 Wiley‐Liss, Inc.