Tumor hypoxia and its downstream effects have remained of considerable interest for decades due to its negative impact on response to various cancer therapies and promotion of metastasis. Diagnosing hypoxia non-invasively can provide a significant advancement in cancer treatment and is the dire necessity for implementing specific targeted therapies now emerging to treat different aspects of cancer. A variety of techniques are being proposed to do so. However, none of them has yet been established in the clinical arena. This review summarizes the methods currently available to assess tumor hypoxia in vivo and their respective advantages and shortcomings. It also points out the impedances that need to be overcome to establish any particular method in the clinic, along with a broad overview of requirements for further advancement in this sphere of cancer research.