During the last few decades, cancer research has focused on the idea that cancer is caused by genetic alterations and that this disease can be treated by reversing or targeting these alterations. The small variations in cancer mortality observed during the previous 30 years indicate, however, that the clinical applications of this approach have been very limited so far. The development of future gene-based therapies that may have a major impact on cancer mortality may be compromised by the high number and variability of genetic alterations recently found in human tumors. This article reviews evidence that tumor cells, in addition to acquiring a complex array of genetic changes, develop an alteration in the metabolism of oxygen. Although both changes play an essential role in carcinogenesis, the altered oxygen metabolism of cancer cells is not subject to the high genetic variability of tumors and may therefore be a more reliable target for cancer therapy. The utility of this novel approach for the development of therapies that selectively target tumor cells is discussed.