The AlkB family of nucleic acid demethylases is currently of intense chemical, biological, and medical interest because of its critical roles in several key cellular processes, including epigenetic gene regulation, RNA metabolism, and DNA repair. Emerging evidence suggests that dysregulation of AlkB demethylases may underlie the pathogenesis of several human diseases, particularly obesity, diabetes, and cancer. Hence there is strong interest in developing selective inhibitors for these enzymes to facilitate their mechanistic and functional studies and to validate their therapeutic potential. Herein we review the remarkable advances made over the past 20 years in AlkB demethylase inhibition research. We discuss the rational design of reported inhibitors, their mode-of-binding, selectivity, cellular activity, and therapeutic opportunities. We further discuss unexplored structural elements of the AlkB subfamilies and propose potential strategies to enable subfamily selectivity. It is hoped that this perspective will inspire novel inhibitor design and advance drug discovery research in this field.