Attachment of oligo-histidine tag (His-tag) to the protein N- or C-terminus is a good example of early and successful protein engineering to design a unique and generalized purification scheme for virtually any protein. Thus relatively strong and specific binding of His-tagged protein is achieved on an Immobilized Metal-Ion Affinity Chromatography (IMAC) matrix. Most popular hexa-histidine tag and recently also deca-histidine tag are used in combination with three chelating molecules: iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), and carboxymethyl aspartic acid (CM-Asp), covalently attached to the chromatographic matrix. ne following combinations with divalent metal ions are preferentially used: (Cu, Zn, Ni, Co)-IDA, Ni-NTA, and Co-CM-Asp. At large scale, regarding cost and product purity, a decisive step is precise and efficient cleavage of His-tag by the cleavage enzyme. Two-step IMAC followed by a polishing step appears to be a minimum but still realistic as an approach to generic technology also for more demanding products. Possible drawbacks in using His-tags and IMAC, such as leaching of metal ions, inefficient cleavage, and batch-to-batch reproducibility must be carefully evaluated before transferred to large scale. Although a great majority of reports refer to small laboratory scale isolations for research purposes it appears there is much higher potential for more extensive use of His-tags and IMAC at large scale than currently documented.