Macromolecular protein and peptide therapeutics have been proven to be effective in treating critical human diseases precisely. Thanks to biotechnological advancement, a huge number of proteins and peptide therapeutics were made their way to pharmaceutical market in past few decades. However, one of the biggest challenges to be addressed for protein therapeutics during clinical application is their fast degradation in serum and quick elimination owing to enzymatic degradation, renal clearance, liver metabolism and immunogenicity, attributing to the short half-lives. Size and hydrophobicity of protein molecules make them prone to kidney filtration and liver metabolism. On the other hand, proteasomes responsible for protein destruction possess the capability of specifically recognizing almost all kinds of foreign proteins while avoiding any unwanted destruction of cellular components. At present almost all protein-based drug formulations available in market are administered intravenously (IV) or subcutaneously (SC) with high dosing at frequent interval, eventually creating dose-fluctuation-related complications and reducing patient compliance vastly. Therefore, artificially increasing the therapeutic half-life of a protein by attaching to it a molecule that increases the overall size (eg, PEG) or helps with receptor mediated recycling (eg, albumin), or manipulating amino acid chain in a way that makes it more prone towards aggregate formation, are some of the revolutionary approaches to avoid the fast degradation in vivo. Half-life extension technologies that are capable of dramatically enhancing half-lives of proteins in circulation (2–100 folds) and thus improving their overall pharmacokinetic (PK) parameters have been successfully applied on a wide range of protein therapeutics from hormones and enzymes, growth factor, clotting factor to interferon. The focus of the review is to assess the technological advancements made so far in enhancing circulatory half-lives and improving therapeutic potency of proteins.