The cancer microenvironment makes up the stroma of the neoplasm and is the tissue that determines tumor growth, progression, and ability to initiate metastases. Because of the role that the cancer microenvironment plays in each stage of tumor development, knowledge about the interactions of the tumor with its microenvironment would seem to be of the utmost importance for developing new treatment strategies. The cancer microenvironment is created by the tissue surrounding the tumor cells and is composed of cells, extracellular matrix, and the proteins of the extracellular matrix. Although tumor cells are capable of penetrating the surrounding stroma, it is the tumor stroma that provides the necessary blood supply and growth factors for the tumor cells that condition tumor growth. In the present review we discuss the role of various cells like tumor-associated macrophages and cancer-associated fibroblasts, expressing RCAS1, B7-H4 molecules, and MT in creating the suppressive profile of the cancer microenvironment and in the cancer microenvironment remodeling that enables both local tumor spread and the creation of metastases.