In the last years it became clear that the tumor microenvironment plays a major role in neoplastic growth. Proteins secreted either by the malignant cells or by the tumor-associated stromal cells act as extracellular signal transductors, orchestrating tumor progression. Sentinel cells of the innate immune system patrol the different organs and have proven either to promote tumor growth or induce tumor suppression. In recent years, members of the matricellular family of extracellular proteins were shown to be involved in different aspects of the inflammatory response during tumor development, although in contradictory ways. In this review we discuss the evidence available up to date that relates matricellular proteins with the regulation of the inflammatory response and tumor progression.