HaloTag technology is comprises of two main elements, the HaloTag protein, a protein fusion tag that can be fused to any protein of interest (POI) genetically and number of various organic molecules, named as HaloTag ligand that binds irreversibly to the HaloTag protein. High impurity as well as low yield has confined the traditional systems for tagging of protein. The conformational and functional alterations can be done by high molecular weight. The Polyhistidine tag has small size. It does not alter protein functions so it is highly recommended for protein analysis. It serves as important tool for protein isolation but has high impurity because of nonspecific binding of other proteins. Histag is effective only for protein isolation and purification so it has been observed that other methodologies should be discovered and applied for cellular imaging. The complexity between protein-protein interactions has limited the research in finding new diagnostic as well as curative or treatment options for various diseases. Moreover, ineffective methods for labelling of protein have restricted the proteomic analysis. Protein purification is an important process but it is time consuming, therefore, new methods are being discovered so that analysis of protein can be done efficiently.