Half-life extension chemical modification of peptides and proteins has become an essential route to enhance the PK profile of biopharmaceuticals. Herein we provide an overview of some important chemical modifications to extend the half-life of biopharmaceuticals, which are alternatives to PEGylation. The emphasis is on chemical moieties, the biophysical properties they direct, and their biological compatibility. One approach to improving the pharmacokinetic properties of peptides relies on chemical moieties that convey protraction by binding to albumin and promote self-assembly to form larger structures. Biopharmaceuticals modified to bind to albumin have an extended mode of action, which in principle can approach the 19-day half-life of albumin. Alternative strategies to improve PK properties rely on covalent conjugation or fusion with long-lived macromolecules with low immunogenicity.