Uterine leiomyoma is a common benign smooth muscle tumor occurring in 20 to 30% of women over 30 years of age. Cytogenetic analysis of such tumors has revealed that over 60% of them have a normal karyotype but also that they sometimes carry recurrent chromosome aberrations, e.g., aberrations involving the short arm of chromosome 6 or the long arm of chromosome 12. Precise mapping of chromosome breakpoints of such recurrent chromosome translocations and molecular characterization of DNA regions immediately flanking such breakpoints have proven to be a successful approach to identify and isolate genes involved in tumor development. Recently, application of such a research strategy on translocations in uterine leiomyoma involving either chromosome 12q13-15 or 6p21 has led to the discovery that two members of the high-mobility group (HMG) protein gene family, HMGIC and HMGIY, are frequently rearranged in such tumors. The developmentally regulated HMGIC and HMGIY genes encode closely related, low-molecular-mass proteins, which are assumed to function as architectural factors in the nuclear scaffold and to be critical in the assembly of stereospecific transcriptional complexes. The frequent rearrangement of the HMGIC and HMGIY genes in uterine leiomyomas suggests that these genes are directly involved in the aberrant growth control observed in these tumors. Studies of a number of other benign solid tumors - most of them in tissues of mesenchymal origin - indicated that involvement of HMGIC is not restricted to uterine leiomyomas, suggesting that benign solid tumor formation might have a common genetic denominator. The possible role of HMG genes in growth control is further supported by results from gene targeting experiments in mice, which indicate that HMGI-C plays an important role in mammalian growth and development, as inactivation of the murine HMGIC gene resulted in the pygmy phenotype. The discovery that high mobility group protein genes might be crucial factors in the formation of uterine leiomyoma provides a new opportunity for developing alternative therapeutic strategies.