Molecular PEGylation has redefined the clinical importance of many biomolecules by improving their pharmacodynamic and pharmacokinetic properties. From its inception, PEGylation has grown substantively into a well-established technology to facilitate the clinical translation of macromolecules by overcoming their limitations. PEGylation renders a number of benefits to therapeutic proteins, such as, increase in hydrodynamic size, extension of circulation half-life, prevention of proteolytic degradation and reduction of immunogenicity and antigenicity. The successful entrance of the PEGylated protein pharmaceuticals to the market, can be ascribed to the unique properties of poly (ethylene glycol) (PEG) conjugated to these proteins. This article aims to review the precise role of PEG in improving the therapeutic efficacy of PEG-protein conjugates approved by regulatory bodies. The data presented herein were extracted from articles published in peer reviewed journals, official websites of manufacturers and safety labeling and drug approval summary of the FDA Centre for Drug evaluation and Research (CDER).