Ubiquitin ligases determine protein stability in a highly regulated manner by coordinating the addition of polyubiquitin chains to proteins that are then targeted to the proteasome for degradation. Ubiquitin ligases have generally been separated into two groups--those containing HECT domains and those with RING finger domains. Recently, a third group of ubiquitin ligases has emerged: those containing a U-box domain. Patterson discusses what is known about the few U-box-containing proteins that have been characterized, although the general properties of U-box proteins that distinguish them from other ubiquitin ligases are still a matter of speculation.