The name for cupin proteins is derived from the Latin term for small barrel, ‘Cupa’. Proteins that belong to the group of cupins adopt a barrel-like structure (Dunwell et al., 2001). According to the database of Structural Classification of Proteins (SCOP) (Murzin et al., 1995), the cupin proteins have been classified as members of ‘RmlC-like Cupins’ superfamily in the ‘Double Stranded Beta Helix’ (DSBH) fold, however, the nomenclature employed in the literature is somewhat ambiguous since JmjC transcription factors (Clissold & Ponting, 2001) display many features typical of the DSBH fold. These common characteristics for the DSBH fold include a pair of four-stranded antiparallel β-sheets constituting up to eight β strands which form the typical β-sandwich structure. The superfamily comprises of 20 families with members performing diverse functions ranging from enzymatic activities like dioxygenases, hydrolases, decarboxylases, epimerases and isomerases to non-enzymatic functions such as binding to auxin, seed storage, and nuclear transcription factors (Dunwell, 2001, 2004). The nature of substrates used in various enzymatic reactions differs in chemical types, size, and structure. The sequence identity is low among the members of this superfamily. The functional site of members of this superfamily is generally located at the center of a conserved barrel. The cupin domain usually consists of two sequence motifs, each corresponding to two -strands. A less conserved region separates these motifs. The conserved motifs, GX5HXHX3,4EX6G and GX5PXGX2HXX3N, together contain the residues involved in metal ion binding at the active site, that is known to play a functional role (Dunwell, 2001, 2004). It has been indicated that 10,346 cupin sequences (Finn et al., 2008) have been identified in 843 species that belong to eukaryotes, prokaryotes, archaebacteria and viruses. In some plant species like O. sativa, V. vinifera and A. thaliana over 100 cupin sequences have been identified. This indicates the extent to which the cupins have diverged and duplicated in proteomes of various species to perform a variety of functions. Various metal ions, bound at the active site, including Iron, Manganese, Nickel, Copper, Zinc and Cadmium are known to play a functional role in the enzymatic members of cupin superfamily (Table 1). The metal cofactor can influence the chemistry of the catalytic reaction. The metal cofactor typically plays an important role in the function of cupins via an interaction with the substrate. An approach involving structure-based clustering of uncharacterized proteins within a group of proteins of known function can provide clues about their possible functions. It thus appears likely that this method would be a valuable tool for the functional annotation of structural genomic target proteins that are similar in structure despite the lack of sequence similarity.