Hypoxia, a decrease in oxygen levels, is a hallmark of solid tumors. Hypoxic cells are more resistant to killing by ionizing radiation and chemotherapy, are more invasive and metastatic, resistant to apoptosis, and genetically unstable. Over the last two decades, the discovery of Hypoxia Inducible Factors, a family of transcription factors crucially involved in the response of mammalian cells to oxygen deprivation, has led to the identification of a molecular target associated with hypoxia suitable for the development of cancer therapeutics. These features of solid tumors may offer a unique opportunity for selective therapeutic approaches. A number of strategies targeting hypoxia and/or Hypoxia Inducible Factors (HIF) have been developed over the last several years and will be described. The exponentially growing interest in therapeutic strategies targeting hypoxia/HIF will undoubtedly generate more active compounds for preclinical and clinical development. A rational development plan aimed to validate target inhibition in preclinical models and early clinical trials is essential for a rapid translation of these agents to the treatment of human cancers.