Protein therapeutics represent a diverse array of biologics including antibodies, fusion proteins, and therapeutic replacement enzymes. Since their inception, they have revolutionized the treatment of a wide range of diseases including respiratory, vascular, autoimmune, inflammatory, infectious, and neurodegenerative diseases, as well as cancer. While in vivo pharmacokinetic, pharmacodynamic, and efficacy studies are routinely carried out for protein therapeutics, studies that identify key factors governing their absorption, distribution, metabolism, and excretion (ADME) properties have not been fully investigated. Thorough characterization and in-depth study of their ADME properties are critical in order to support drug discovery and development processes for the production of safer and more effective biotherapeutics. In this review, we discuss the main factors affecting the ADME characteristics of these large macromolecular therapies. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of recombinant biotherapeutic drugs, and demonstrate how ADME studies will facilitate their future development.