Since its discovery in 1981, ubiquitin-activating enzyme 1 was thought to be the only E1-type enzyme responsible for ubiquitin activation. Recently, a relatively uncharacterized E1 enzyme, designated ubiquitin-like modifier activating enzyme 6, was also shown to activate ubiquitin. Ubiquitin-activating enzyme 1 and ubiquitin-like modifier activating enzyme 6 are both essential proteins, and each uses a different spectrum of ubiquitin-conjugating (E2) enzymes. Ubiquitin-like modifier activating enzyme 6 activates not only ubiquitin, but also the ubiquitin-like modifier FAT10 (human leukocyte antigen F-associated transcript 10), which, similarly to ubiquitin, serves as a signal for proteasomal degradation. This new layer of regulation in ubiquitin activation markedly increases the versatility of the ubiquitin conjugation system.