MEF2C is a selectively expressed transcription factor involved in different transcriptional complexes. Originally identified as an essential regulator of muscle development, ectopic expression of MEF2C as a result of chromosomal rearrangements is now linked to leukemia. Specifically, high MEF2C expression has been linked to mixed lineage leukemia-rearranged acute myeloid leukemia as well as to the immature subgroup of T-cell acute lymphoblastic leukemia. This review focuses on the role of MEF2C in the hematopoietic system and on aberrant MEF2C expression in human leukemia.