Accumulating recent evidence supports the notion that many enzymes that modify histones are fundamental players in normal hematopoiesis as well as hematologic malignancies, and represent an important new class of drug targets. Histone H3 lysine 4 (H3K4) methylation plays several distinct roles in gene expression and is modulated by specific methyltransferases and demethylases. Recent progress has been made clarifying the unique biological roles of the enzymes that carry out H3K4 methylation, yet a detailed understanding of H3K4 methylation states in various genomic contexts and the diverse functions of the enzymes that perform these methylation events is incomplete, but developing rapidly. In this review, we summarize and discuss the general mechanisms of H3K4 methylation, and how the six main enzymes from the SET/MLL family (responsible for H3K4me1/me2/me3) function in hematopoiesis and in hematologic malignancies.