Activated oncogenes and disrupted tumor suppressor genes (TSGs) not only endow aspiring cancer cells with new biological capabilities but also influence the composition and function of host cells in the tumor microenvironment (TME). These non-cancer host cells can in turn provide cancer cells with growth support and protection from the anti-tumor immune response. In this ecosystem, geospatially heterogenous “subTME” adds to the complexity of the “global” TME which bestows tumors with increased tumorigenic ability and resistance to therapy. This review highlights how specific genetic alterations in cancer cells establish various symbiotic co-dependencies with surrounding host cells and details the cooperative role of the host cells in tumor biology. These essential interactions expand the repertoire of targets for the development of precision cancer treatments.