Evolutionary conservation has become a powerful tool to identify functionally important genomic sequences/elements in the human genome. There are 481 genomic segments longer than 200 base pairs (bp) that are absolutely conserved (100% identity with no insertions or deletions) between human, mouse and rat genomes. Such segments are known as ultraconserved elements (UCEs). Although our knowledge of UCEs is limited, most recent studies suggest that UCEs play a functional role in vertebrate genomes, such as serving as long-range enhancers of flanking genes, regulating splicing and epigenetic modifications, and functioning as transcriptional coactivator. Most recent studies show that expression of UCEs is consistently altered in tumors, strongly suggesting these elements may also be involved in human disease such as cancer development.