Transcription factors control expression of genes essential for the normal functioning of the hematopoietic system and regulate development of distinct blood cell types. During leukemogenesis, aberrant regulation of transcription factors such as RUNX1, CBFβ , MLL, C/EBPα, SPI1, GATA and TAL1 is central to the disease. Here, we will discuss the mechanisms of transcription factor deregulation in leukemia and how in recent years next generation sequencing approaches have helped to elucidate the molecular role of many of these aberrantly expressed transcription factors. We will focus on the complexes in which these factors reside, the role of post translational modification of these factors, their involvement in setting up higher order chromatin structures as well as their influence on the local epigenetic environment. We suggest that only comprehensive knowledge on all these aspects will increase our understanding of aberrant gene expression in leukemia as well as open new entry points for therapeutic intervention.