The hypoxic tumor microenvironment represents a persistent obstacle in the treatment of most solid tumors. In the past years, significant efforts have been made to improve the efficacy of anti-cancer drugs. Therefore, hypoxia-activated prodrugs (HAPs) of chemotherapeutic compounds have attracted widespread interest as a therapeutic means to treat hypoxic tumors. This updated review paper covers key patents published between 2006 and 2021 on the developments of HAP derivatives of anti-cancer compounds. Despite significant achievements in the development of HAP derivatives of anti-cancer compounds and although many clinical trials have been performed or are ongoing both as monotherapies and as part of combination therapies, there has currently no HAP anti-cancer agent been commercialized into the market. Unsuccessful clinical translation is partly due to the lack of patient stratification based on reliable biomarkers that are predictive of a positive response to hypoxia-targeted therapy.