The transcription factor CCAAT/enhancer binding protein α (C/EBPα), as a critical regulator of myeloid development, directs granulocyte and monocyte differentiation. Various mechanisms have been identified to explain how C/EBPα functions in patients with acute myeloid leukemia (AML). C/EBPα expression is suppressed as a result of common leukemia-associated genetic and epigenetic alterations such as AML1-ETO, RARα-PLZF or gene promoter methylation. Recent data have shown that ubiquitination modification also contributes to its downregulation. In addition, 10-15% of patients with AML in an intermediate cytogenetic risk subgroup were characterized by mutations of the C/EBPα gene. As a transcription factor, C/EBPα can translocate into the nucleus and further regulate a variety of genes directly or indirectly, which are all key factors for cell differentiation. This review summarizes recent reports concerning the dysregulation of C/EBPα expression at various levels in human AML. The currently available data are persuasive evidence suggesting that impaired abnormal C/EBPα expression contributes to the development of AML, and restoration of C/EBPα expression as well as its function represents a promising target for novel therapeutic strategies in AML.