Since its discovery over three decades ago, it has become abundantly clear that the ubiquitin (Ub) system is a quintessential feature of all aspects of eukaryotic biology. At the heart of the system lies the conjugation and deconjugation of Ub and Ub-like (Ubls) proteins to proteins or lipids drastically altering the biochemistry of the targeted molecules. In particular, it represents the primary mechanism by which protein stability is regulated in eukaryotes. Ub/Ubls are typified by the β-grasp fold (β-GF) that has additionally been recruited for a strikingly diverse range of biochemical functions. These include catalytic roles (e.g., NUDIX phosphohydrolases), scaffolding of iron-sulfur clusters, binding of RNA and other biomolecules such as co-factors, sulfur transfer in biosynthesis of diverse metabolites, and as mediators of key protein-protein interactions in practically every conceivable cellular context. In this chapter, we present a synthetic overview of the structure, evolution, and natural classification of Ub, Ubls, and other members of the β-GF. The β-GF appears to have differentiated into at least seven clades by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions. The β-GF appears to have first emerged in the context of translation-related RNA-interactions and subsequently exploded to occupy various functional niches. Most biochemical diversification of the fold occurred in prokaryotes, with the eukaryotic phase of its evolution mainly marked by the expansion of the Ubl clade of the β-GF. Consequently, at least 70 distinct Ubl families are distributed across eukaryotes, of which nearly 20 families were already present in the eukaryotic common ancestor. These included multiple protein and one lipid conjugated forms and versions that functions as adapter domains in multimodule polypeptides. The early diversification of the Ubl families in eukaryotes played a major role in the emergence of characteristic eukaryotic cellular substructures and systems pertaining to nucleo-cytoplasmic compartmentalization, vesicular trafficking, lysosomal targeting, protein processing in the endoplasmic reticulum, and chromatin dynamics. Recent results from comparative genomics indicate that precursors of the eukaryotic Ub-system were already present in prokaryotes. The most basic versions are those combining an Ubl and an E1-like enzyme involved in metabolic pathways related to metallopterin, thiamine, cysteine, siderophore and perhaps modified base biosynthesis. Some of these versions also appear to have given rise to simple protein-tagging systems such as Sampylation in archaea and Urmylation in eukaryotes. However, other prokaryotic systems with Ubls of the YukD and other families, including one very close to Ub itself, developed additional elements that more closely resemble the eukaryotic state in possessing an E2, a RING-type E3, or both of these components. Additionally, prokaryotes have evolved conjugation systems that are independent of Ub ligases, such as the Pup system.