The environment that surrounds a tumor is largely defined as its microenvironment. It consists of the immediate surrounding (or infiltrated) cells which include stroma and immune cell. Those can either protect or be part of the hostile environment that defines tumor ability to survive. Other central components within the tumor microenvironment include the level of oxygen (hypoxia), nutrients and drugs (chemotherapy) that overall generate a hostile environment the tumor cells must survive, or die. To survive inhospitable environments, tumor cells are forced to remodel their signaling pathways by altering transcription, translation, and post-translational modifications. This remodeling known as adaptation, is regulated in a spatial and temporal manner and gives rise to individual tumor cells with distinct gene expression and metabolic signatures. Such phenotypic heterogeneity is the result of tumor cell plasticity, which—together with the genetic background of the tumor—determines whether cells resist environmental stress, enter dormancy, or metastasize. Tumor cells exploit the cellular stress response to balance proliferation, differentiation, and survival signals, and to remodel local and distant environments.