Hypermethylated in cancer (HIC-1) was originally identified as a target of p53-induced gene expression. HIC-1 is deleted in the genetic disorder Miller-Dieker syndrome (MDS), and the expression of HIC-1 is also frequently suppressed in leukemia and various cancers due to the hypermethylation of specific DNA regions and the resulting transcriptional silencing. These and other studies indicate that HIC-1 acts as a putative tumor suppressor protein that mediates transcriptional repression. HIC-1 is ubiquitously expressed in adult tissues and its structure is defined by five zinc fingers and an N-terminal broad complex POZ (or BTB) domain. In several BTB POZ containing proteins, including BCL-6 and the promyelocytic leukemia zinc-finger (PLZF) oncoprotein, this domain interacts with the SMRT N-CoR-mSin3A HDAC complex and is directly involved in repressing and silencing gene transcription. When this domain is deleted, as with the oncogenic PLZF-RAR chimera of promyelocytic leukemias, this transcriptional repression is attenuated. Conversely, HIC-1 does not interact with components of the HDAC complex, suggesting that HIC-1-induced transcriptional repression is unassociated with the POZ BTB domain.