The clinical use of proteins as therapeutic agents is not a recent development. Even when one excludes the obvious field of vaccines, it is possible to trace the origins of some modern protein therapies back more than one hundred years. The earliest applications primarily involved tissue extracts containing unidentified components. Most often a “beneficial activity” was the actual therapeutic rather than specific agent. Hence, insulin entered the clinic in the 1920s as an anti-diabetic activity found in pancreatic extracts and it would be 50 years before purified protein became available. Problems associated with this approach were numerous. Availability, reproducibility of activity, stability, immunogenicity (when proteins of other species were used) were common difficulties and, more importantly, the lack of defined pharmacologic parameters often lead to unpredictable responses. Even when the active factors were unambiguously identified as proteins, these problems often remained. For example, until 1985 extracts of cadaver pituitary glands were the primary source of human somatotropin for the treatment of growth hormone deficiencies. The deaths of several patients from Creutzfeldt-Jakob disease attributed to possible contamination of the protein with a slow acting neurotropic virus, however, lead to the exclusion of pituitary extracts as a source of this hormone.