Abstract: Although histone H3 Lysine 4 methylation (H3K4me) is strongly associated with active transcription, an increasing number of arguments indicate its repressive role in gene expression. Recent data in the mammalian and budding yeast systems have provided evidence for H3K4me2 and H3K4me3 tethering histone deacetylase complexes (HDACs) to modulate gene expression. In S. cerevisiae, this regulation is mediated by specific subunits within HDACs that recognize the methylation status of H3K4 allowing chromatin reorganization to attenuate or repress transcription. Albeit we are still a long way from understanding the mechanism and biological consequences, it is becoming clear that H3K4me at certain chromatin loci may prevent aberrant gene expression or modulate transcriptional response. This review will provide a brief overview of a novel interpretation of H3K4me and its outcome on transcription regulation and will suggest future challenges for the field of epigenetics.