HNF-4α is a member of the steroid hormone receptor family of transcription factors with roles in the development of the liver and the regulation of several critical metabolic pathways, such as glycolysis, drug metabolism, apolipoproteins and blood coagulation. The transcriptional potency of HNF-4α is well known due to its involvement in diabetes and other metabolic diseases. However, recently HNF-4α has been discovered to be closely associated with several haematological disorders, mainly because of genetic mutations, drugs, and hepatic disorders. We review HNF-4α structure and function, and its role in haematological disorders. We discuss possible novel therapies that are based on targeting HNF-4α.