The purpose of making a “biobetter” biologic is to improve on the salient characteristics of a known biologic for which there is, minimally, clinical proof of concept or, maximally, marketed product data. There already are several examples in which second-generation or biobetter biologics have been generated by improving the pharmacokinetic properties of an innovative drug, including Neulasta^® [a PEGylated, longer-half-life version of Neupogen^® (filgrastim)] and Aranesp^® [a longer-half-life version of Epogen^® (epoetin-α)]. This review describes the use of protein fusion technologies such as Fc fusion proteins, fusion to human serum albumin, fusion to carboxy-terminal peptide, and other polypeptide fusion approaches to make biobetter drugs with more desirable pharmacokinetic profiles.