Publisher Summary This chapter discusses the recent developments in the field of enzyme replacement therapy, describes the successes achieved, and indicates procedures that are expected to improve prospects for enzyme replacement therapy in the future. The first investigation of direct enzyme replacement in a human lipid storage disorder was performed in a patient with metachromatic leukodystrophy who received partially purified arylsulfatase A, using human urine as the source of the enzyme. The preparation was injected into the patient's spinal canal and caused a severe pyrogenic reaction. The first investigation of enzyme replacement in a ganglioside storage disorder was carried out in 1971 when a patient with the Sandhoff form of Tay-Sachs disease was infused with hexosaminidase A isolated from human urine. However, because of the inability to deliver enzymes to the brain, enzyme replacement seemed to be practicable only in disorders in which systemic organs and tissues were involved. The first recipients of glucocerebrosidase, which was isolated from human placental tissue in sufficient purity for human trials, were a young male with Type 3 (juvenile) Gaucher's disease and a female with Type 1 Gaucher's disease. Liver biopsies performed before and after the enzyme was infused, indicated that about 26% of the stored glucocerebroside in the liver had been catabolized in both patients. The second patient had accumulated twice the amount of glucocerebroside in her liver as the first. The level of glucocerebroside in the blood of both recipients gradually returned from a 3-fold elevation to the normal value over a period of 72 hr and remained normal over a period of many months.