The importance of tumor microenvironmental in malignant progression has been largely ignored. Tumor cells protect themselves from changes in the microenvironment due to a decrease in nutrients and oxygen by reducing macromolecular synthesis and inducing genes that will promote angiogenesis and tissue remodeling. This ability of transformed cells to survive fluctuations in oxygen tensions is clinically important, as tumors with high hypoxic fractions respond poorly to many forms of cancer therapy. While it is commonly accepted that the decrease in molecular oxygen in hypoxic cells makes them more refractory to killing by agents such as ionizing radiation which use oxygen radical formation, the cessation of division and loss of apoptotic (cell suicide) potential in hypoxic cells are also important in their resistance to killing by radiotherapy and chemotherapy. In this chapter, we will discuss hypoxia-induced stress proteins in regards to three clinically relevant end points: inhibition of cell proliferation, induced of apoptosis, and regulation of genes modulating angiogenesis. Although these three end points may seem unrelated, in fact, they are intimately linked with each other in the cellular response to hypoxia and malignant progression. One of the goals of this review is to inform both clinician and scientist of these interrelationships and discuss how hypoxia selects for tumors that are clonal expansions of cells that have lost their apoptotic ability and have switched to a proangiogenic phenotype.