Tumor microenvironment (TME) is important in tumor development and may be a target for anti-cancer therapy. The genesis of TME is a dynamic process that is regulated by intrinsic and extrinsic factors and coordinated by multiple genes, cells, and signal pathways. Cancer anaerobic metabolism and various oncogenes may stimulate the genesis of TME. Tumor cells and cancer stem cells actively participate in the genesis of the cancer stem cell niche and tumor neovascularization, important in the initiation of the TME. Various cancer-associated stromal cells, derived niche factors, and tumor-associated macrophages may function as promoters in the genesis of the TME. Dicer1 gene-deleted stromal cells can induce generation of cancer stem cells and initiate tumorigenesis, suggesting that stromal cells also may promote the genesis of the TME. Therefore, the key features of TME include niche-driving oncogenes, cancer anaerobic metabolism, niche-driving cancer stem cells, neovascularization, tumor-associated inflammatory cells, and cancer-associated stromal cells. These features are potential targets for normalization of the malignant TME and effective anti-cancer therapy.