An elaborate array of heterogeneous populations consisting of neoplastic cells, as well as recruited mesenchymal and inflammatory cells, form the tumor-associated stroma, a pathological milieu collectively known as the tumor microenvironment (TME). Although the traditional approach portrays carcinogenesis as the sum of genetic and epigenetic alterations that tumor cells undergo during the course of the multistep pathological process, over the last two decades, the TME has also been discovered to play an equally important role in determining tumor behavior. Broadly, the paracrine interactions that take place between tumor cells and the TME were found to influence the overall homeostasis, facilitating cancer growth and progression. The neoplastic evolution often benefits from the selective conditions of the TME, among them the presence of cancer-associated fibroblasts (CAFs), abnormal extracellular matrix (ECM) deposition, chronic inflammation, expanded vascularization, and immune response repression. This chapter will point out the main cellular and acellular components of the TME, focusing particular attention on how these tumor-derived factors and the underlying pathophysiological processes mentioned above play a role in innately modulating all aspects of cancer progression, starting with primary tumor growth and reaching the metastatic phase.