Uterine leiomyomata, or fibroids, represent the most common tumor in women of reproductive age. Although benign, leiomyomata constitute a major health problem, and are the most frequent indication for hysterectomy. The pathobiology of these tumors is still poorly understood. Cytogenetic and genetic studies have, in recent years, advanced our understanding of the etiology of these tumors. Specifically, cytogenetic aberrations involving chromosomes 6, 7, 12 and 14 have been shown to constitute the major chromosomal abnormalities seen in leiomyomata and have led to the discovery that HMGIC and HMGIY, two members of the non-histone high mobility group of genes, are involved in fibroid development. HMGIC and HMGIY map to 12q15 and 6p21, and their disruption or dysregulation has been shown to contribute to leiomyomata formation. Given the observation of several additional, but consistent, chromosomal aberrations, it is likely that other genes with fundamental roles in the pathobiology of uterine leiomyomata await identification. Furthermore, twin studies and the discovery of both ethnic and familial predispositions have suggested a genetic liability to develop uterine leiomyomata.