This chapter provides a critical overview of the technology presently available in the field of protein PEGylation. The chemistry of the polymer and of its reactive derivatives is discussed and presented together with several protocols used to obtain PEG-protein conjugates. The coupling protocols are critically discussed on the basis of the properties of the protein to be modified and those desired for the final product. Methods for product purification and characterization are also provided. The overall information provided will guide the reader toward all of the critical steps involved in the preparation of PEG-protein adducts.