Known histone deacetylases (HDACs) are divided into different classes, and HDAC3 belongs to Class I. Through forming multiprotein complexes with the corepressors SMRT and N-CoR, HDAC3 regulates the transcription of a plethora of genes. A growing list of nonhistone substrates extends the role of HDAC3 beyond transcriptional repression. Here, we review data on the composition, regulation and mechanism of action of the SMRT/N-CoR-HDAC3 complexes and provide several examples of nontranscriptional functions, to illustrate the wide variety of physiological processes affected by this deacetylase. Furthermore, we discuss the implication of HDAC3 in cancer, focusing on leukemia. We conclude with some thoughts about the potential therapeutic efficacies of HDAC3 activity modulation.