Solid tumors are known to develop microenvironmental hypoxia or anoxia due to malfunction and malformation of blood vessels and the energy demands of the highly proliferative tumor cells. Oxygen deprivation can cause aberrant modifications of signaling pathways and their downstream transcription factors that are believed to contribute to malignancy. Here, we review the latest studies related to the involvement of hypoxia-inducible transcription factor-1alpha (HIF-1alpha), the first known mammalian intracellular hypoxia sensor, in tumor development. We propose that a second far less studied protein, metal transcription factor-1 (MTF-1), acts as a more general oxygen sensor, responding to both hypoxia and oxidative stress, and is also intimately involved in malignant progression. Existing evidence suggests that activation of these two ubiquitous proteins, by hypoxia and genetic modifications, modulate the expression patterns of a number of important proteins involved in tumorigenesis.