HIC1 (Hypermethylated in Cancer 1), as it name implied, was originally isolated as a new candidate tumor suppressor gene located at 17p13.3 because it resides in a CpG island that is hypermethylated in many types of human cancers. HIC1 encodes a transcription factor associating an N-terminal BTB/POZ domain to five C-terminal Krüppel-like C(2)H(2) zinc finger motifs. In this review, we will begin by providing an overview of the current knowledge on HIC1 function, mainly gained from in vitro studies, as a sequence-specific transcriptional repressor interacting with a still growing range of HDAC-dependent and HDAC-independent corepressor complexes. We will then summarize the studies that have demonstrated frequent hypermethylation changes or losses of heterozygosity of the HIC1 locus in human cancers. Next, we will review animal models which have firmly established HIC1 as a bona fide tumor suppressor gene epigenetically silenced and functionally cooperating notably with p53 within a complex HIC1-p53-SIRT1 regulatory loop. Finally, we will discuss how this epigenetic inactivation of HIC1 might "addict" cancer cells to altered survival and signaling pathways or to lineage-specific transcription factors during the early stages of tumorigenesis.