Enzyme replacement therapy for the lysosomal storage disorders derives its impetus from the successes achieved in the treatment of Gaucher disease. After nearly two decades of persistent but unsuccessful efforts, the promise of therapy through enzyme replacement was losing credibility. Then, the fortunate intersection of two different lines of scientific research produced the necessary breakthrough. The dramatic responses to enzyme replacement therapy in patients with Gaucher disease made it immediately clear that this treatment approach was a success. Furthermore, the large number of patients with the disorder guaranteed commercial involvement. The lessons learned from the development of enzyme replacement therapy for Gaucher disease are broadly applicable to other lysosomal storage diseases and will be reviewed in this paper.