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Although ubiquitin is the most well studied and understood functional protein post-translational modifier, there is a growing family of ubiquitin-like modifiers (UBLs/Modifiers) that also may modify cellular targets to influence diverse biological processes. Members of the ubiquitin and UBL protein family include ubiquitin, SUMO, NEDD8, ISG15, URM1, FAT10, UFM1, and ATG12. These related proteins are structurally similar, and are activated, conjugated, and released from conjugates in a mechanism akin to that for ubiquitin. There is cross-talk between conjugation pathways with some substrate proteins becoming targeted by more than one type of modifier. Ubiquitin is found only in eukaryotic organisms in which it shows strong sequence conservation. Ubiquitin is present in all cell types and found both in free form and conjugated to proteins, by a process known as ‘ubiquitylation’ or ‘ubiquitination’.