Epigenetic mechanisms are fundamental to understanding the regulatory networks of gene expression that govern stem cell maintenance and differentiation. Methylated histone H3 lysine 4 (H3K4) has emerged as a key epigenetic signal for gene transcription; it is dynamically modulated by several specific H3K4 methyltransferases and demethylases. Recent studies have described new epigenetic mechanisms by which H3K4 methylation modifiers control self-renewal and lineage commitments of stem cells. Such advances in stem cell biology would have a high impact on the research fields of cancer stem cell and regenerative medicine. In this review, we discuss the recent progress in understanding the roles of H3K4 methylation modifiers in regulating embryonic and adult stem cells' fates.