HMGI(Y) and HMGI-C are members of a distinct family of “high mobility group” (HMG) proteins that are nonhistone chromatin-associated proteins initially characterized by high electrophoretic mobility in polyacrylamide gels (hence the acronym HMG). Recent studies have shown that HMGI(Y) and HMGI-C are important elements with a role in the regulation of chromatin structure and function. Like other HMG proteins they are responsible for the correct three-dimensional configuration of protein-DNA complexes and therefore play a key role in important cellular processes such as DNA transcription. Aberrant HMGI(Y) and HMGI-C expression generally correlates with a malignant tumor phenotype. However, HMGI(Y) and HMGI-C dys-regulation, as a result of specific chromosomal rearrangements, is also being identified in a variety of common benign mesenchymal tumors such as lipomas and uterine leiomyomas making HMGI(Y) and HMGI-C genes probably the most commonly rearranged genes in human neoplasms. While a precise definition of the HMGI(Y) and HMGI-C role in tumor initiation and progression is still missing, it is likely that future investigations will contribute valuable insights to the understanding of human neoplasia.