Protein therapeutics represent a powerful class of clinically approved drugs for the prevention and treatment of various diseases. Once administered, the biological fate of protein therapeutics is governed by the body's various complex biochemical and biophysical clearance mechanisms, several of which may decrease the drug's circulation time and efficiency. In this tutorial review, we introduce the concepts of physiological protein clearance from the body, and describe several chemical modification and protein engineering approaches used to improve the life span of administered protein therapeutics.