Following the discovery of ubiquitin, many additional evolutionarily related members of the group were described, involving parallel regulatory processes and similar chemistry.

[9] A systematic survey has since identified over 10,000 distinct genes for ubiquitin or ubiquitin-like proteins represented in eukaryotic genomes.

[10] Members of the UBL family are small, non-enzymatic proteins that share a common structure exemplified by ubiquitin, which has 76 amino acid residues arranged into a "beta-grasp" protein fold consisting of a five-strand antiparallel beta sheet surrounding an alpha helix.

[17] Some UBL families and their associated regulatory proteins in plants have undergone dramatic expansion, likely due to both whole genome duplication and other forms of gene duplication; the ubiquitin, SUMO, ATG8, and MUB families have been estimated to account for almost 90% of plants' UBL genes.

[19][20] Recently, a seemingly complete set of genes corresponding to a eukaryote-like ubiquitin pathway was identified in an uncultured archaeon in 2011,[22][23][24] and at least three lineages of archaea—"Euryarchaeota", Thermoproteota (formerly Crenarchaeota), and "Aigarchaeota"—are believed to possess such systems.

[27][28] Regulation of UBLs that are capable of covalent conjugation in eukaryotes is elaborate but typically parallel for each member of the family, best characterized for ubiquitin itself.

The result of this process is the formation of a covalent bond between the C-terminus of ubiquitin and a residue (typically a lysine) on the target protein.

[1] The best known function of ubiquitin is identifying proteins to be degraded by the proteasome, but ubiquitination can play a role in other processes such as endocytosis and other forms of protein trafficking, transcription and transcription factor regulation, cell signaling, histone modification, and DNA repair.

[39] Phylogenetic studies of the beta-grasp protein fold superfamily suggest that eukaryotic UBLs are monophyletic, indicating a shared evolutionary origin.

[13] UBL regulatory systems - including UBLs themselves and the cascade of enzymes that interact with them - are believed to share a common evolutionary origin with prokaryotic biosynthesis pathways for the cofactors thiamine and molybdopterin; the bacterial sulfur transfer proteins ThiS and MoaD from these pathways share the beta-grasp fold with UBLs, while sequence similarity and a common catalytic mechanism link pathway members ThiF and MoeB to ubiquitin-activating enzymes.

[11][40] Comparative genomics surveys of UBL families and related proteins suggest that UBL signaling was already well-developed in the last eukaryotic common ancestor and ultimately originates from ancestral archaea,[15] a theory supported by the observation that some archaeal genomes possess the necessary genes for a fully functioning ubiquitination pathway.