TAL1/SCL (hereafter referred to as TAL1) is a critical transcription factor required for hematopoiesis in which hematopoietic stem cells commit and differentiate to different lineages. During this process, transcription of many genes is turned on and off in part by epigenetic mechanisms. TAL1 has recently been shown to differentially recruit LSD1 and other histone modifying complexes to regulate its target genes. Here, we focus primarily on epigenetic mechanisms that are regulated by TAL1 during normal and malignant hematopoiesis. We discuss how different histone modifying enzymes are recruited by TAL1 and how these enzymatic activities mediate the activating or repressive function of TAL1. Finally, we further explore the possible mechanisms by which dysregulation of the recruitment and activity of histone modifying enzymes contribute to leukemogenesis.