Photodynamic therapy (PDT) is considered a promising approach for the treatment of cancer and is achieved via the photosensitizer (PS)-mediated incomplete reduction of oxygen upon light irradiation, which generates high levels of reactive oxygen species (ROS) to induce potent vascular damage and to directly kill tumor cells. However, there is an undesirable impediment with this approach in that tumor tissues generally suffer from serious hypoxia, which significantly affects the efficiency of PDT. Additionally, PDT that consumes oxygen will further aggravate tumor hypoxia, thus potentially leading to multiple undesirable consequences, such as angiogenesis, tumor invasiveness, and tumor metastasis. This mini-review provides a comprehensive overview of the recent research progress on overcoming or utilizing tumor hypoxia to enhance the therapeutic efficacy of PDT.