Colorectal cancer (CRC) whit more than a million of new cases per year is one of the most common registered cancers worldwide with few treatment options especially for advanced and metastatic patients.The tumor microenvironment is composed by extracellular matrix (ECM), cells, and interstitial fluids. Among all these constituents, in the last years an increased interest around the ECM and its potential role in cancer tumorigenesis is arisen. During cancer progression the ECM structure and composition became disorganized, allowing cellular transformation and metastasis. Up to now, the focus has mainly been on the characterization of CRC microenvironment analyzing separately structural ECM components or cell secretome modifications. A more extensive view that interconnects these aspects should be addressed. In this review, biochemical (secretome) and biomechanical (structure and architecture) changes of tumor microenvironment will be discussed, giving suggestions on how these changes can affect cancer cell behavior. J. Cell. Physiol. 232: 967–975, 2017. © 2016 Wiley Periodicals, Inc. In this review we discuss how changes in one of the major components of tumoral niche, the extracellular matrix (ECM), allow disease initiation, progression and aggressiveness. The ECM remodeling process in colorectal cancer is presented here considering the alterations occurring in the architecture/structure and in the secretome composition, giving suggestions of new interesting markers of aggressiveness. A comprehensive view of the interactions between tumor cells and ECM should be further investigate in the future to provide new and helpful markers of patients’ response to therapy.