Recent studies have revealed that chromatin remodeling, caused by DNA methylation and histone modifications such as acetylation, methylation, and phosphorylation, plays a pivotal role in DNA replication/repair and the regulation of epigenetic gene expression. Among the posttranscriptional histone modifications, lysine methylation is one of the most widely studied, and methylation at various sites provides functional diversity due to mono-, di-, or trimethylation of the ε-amino group of lysine residues. Histone lysine methylation had been regarded as irreversible, but since 2004, two classes of histone lysine demethylases (KDMs) have been identified: lysine-specific demethylase 1/2 (LSD1/LSD2), which are flavin-dependent amine oxidase domain-containing enzymes, and Jumonji domain-containing protein (JMJD) histone demethylases, which are Fe(II) and α-ketoglutarate-dependent enzymes, establishing that histone methylation is reversibly regulated by histone lysine methyltransferases (HKMTs) and KDMs. As there is increasing evidence that KDMs are associated with various disease states, they have emerged as attractive targets for the development of new therapeutic drugs. To date, several classes of KDM inhibitors have been identified. In this Perspective, we review the reported KDM inhibitors and discuss their potential as therapeutic agents.