Reversible histone lysine methylation is a major mechanism for regulating chromatin dynamics and gene expression. Histone demethylases (EC 1.14.11.) are believed to be involved in tumor-suppressive activities. These are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. Until recently, the absence of any selective inhibitors hampered the elucidation of the biological relevance of the demethylase activity of JMJ enzymes in regulating cellular responses. The discovery of the selective inhibitors GSK J1 and its ethyl ester prodrug GSK J4 (Axon 1934 and 1933 resp.) has recently shown the importance as critical determinants of pro-inflammatory gene activation in human primary macrophages.The mono- and di-methyl lysine demethylase (LSD1 or KDM1A; EC 1.14.11.xx) is a flavin-bound epigenetic enzyme that oxidatively cleaves methyl groups from monomethyl and dimethyl Lys4 of histone H3 (H3K4Me1, H3K4Me2) and can contribute to gene silencing. Based on its enzymatic mechanism, LSD1 cannot demethylate trimethylated H3K4Me3, but members of the iron-dependent JMJ histone demethylases are known to serve this function. LSD1 is highly expressed in patients with acute myloid leukemia AML, and its overexpression has been implicated in various other tumors. Collectively, these data predicted that the use of small-molecule inhibitors that target LSD1 could result in epigenetic reprogramming that enhanced or facilitated the execution of the ATRA-induced differentiation program in AML cells.