Adenosine kinase (ADK, EC: 2.7.1.20) is an evolutionarily ancient ribokinase, which acts as a metabolic regulator by transferring a phosphoryl group to adenosine to form AMP. The enzyme is of interest as a therapeutic target because its inhibition is one of the most effective means to raise the levels of adenosine and hence adenosine receptor activation. For these reasons, ADK has received significant attention in drug discovery efforts in the early 2000s for indications such as epilepsy, chronic pain, and inflammation; however, the report of adverse events regarding cardiovascular and hepatic function as well as instances of microhemorrhage in the brain of preclinical models prevented further development efforts. Recent findings emphasize the importance of compartmentalization of the adenosine system reflected by two distinct isoforms of the enzyme, ADK-S and ADK-L, expressed in the cytoplasm and the cell nucleus, respectively. Newly identified adenosine receptor independent functions of adenosine as a regulator of biochemical transmethylation reactions, which include DNA and histone methylation, identify ADK-L as a distinct therapeutic target for the regulation of the nuclear methylome. This newly recognized role of ADK-L as an epigenetic regulator points toward the potential disease-modifying properties of the next generation of ADK inhibitors. Continued efforts to develop therapeutic strategies to separate nuclear from extracellular functions of adenosine would enable the development of targeted therapeutics with reduced adverse event potential. This review will summarize recent advances in the discovery of novel ADK inhibitors and discuss their potential therapeutic use in conditions ranging from epilepsy to cancer.