The transcription factor RUNX1 is essential for correct hematopoietic development as in its absence in the germ line blood stem cells are not formed. RUNX1 orchestrates dramatic changes in the chromatin landscape at the onset of stem cell formation which set the stage for both stem self-renewal and further differentiation. However, once blood stem cells are formed, the mutation of the RUNX1 gene is not lethal but can lead to various hematopoietic defects and a predisposition to cancer. Here we summarize the current literature of inherited and acquired RUNX1 mutations with a particular emphasis on mutations that alter the structure of the RUNX1 protein itself and place these changes in the context of what is known about RUNX1 function. We also summarize which mutant RUNX1 proteins are actually expressed in cells and discuss the molecular mechanism of how such variants reprogram the epigenome setting stem cells on the path to malignancy.