The family of matricellular proteins comprises molecules with disparate biology. The main characteristic of matricellular proteins is to be expressed during tissue renewal and repair in order to “normalize” the tissue. Tumors are wound that do not heal, and tumor growth and metastasis can be viewed as a consequence of aberrant homeostasis, during which matricellular proteins are often upregulated. In the tumor microenvironment, they can be produced by both tumor cells and surrounding stromal cells, such as fibroblasts and macrophages. In this context, matricellular proteins can exert several functions that actively contribute to tumor progression. They may (a) regulate cellular adhesion and migration and extracellular matrix deposition, (b) control tumor infiltration by macrophages or other leukocytes, (c) affect tumor angiogenesis, (d) regulate TGFβ and other growth factor receptor signals, (e) directly stimulate integrin receptors to transduce pro-survival or pro-migratory signals, and (f) regulate the wnt/β-catenin pathways. Most of these functions contribute to settle a chronic low inflammatory state, whose involvement in tissue transformation and tumor progression is now established.