Transcription factors play a crucial role in myeloid differentiation and lineage determination. Tumour suppressor protein C/EBPalpha is a key regulator of granulocytic differentiation whose functional inactivation has become a pathophysiological signature of myeloid leukaemia. In this review we describe various mechanisms such as antagonistic protein-protein interaction, mutation and posttranslational modifications of C/EBPalpha which lead to its transcriptional inhibition and render C/EBPalpha inactive in its functions.