The history of treatment of Gaucher disease started with splenectomy and continued with bone marrow transplantation, before the recent introduction of enzyme replacement therapy. Although the latter has revolutionized the prognosis of patients, many questions remain to be answered and clinical management problems resolved. These include how to monitor enzyme replacement to determine the optimal dosage, how to treat mild disease, whether intermittent treatment is an option, and the causes of the neurological signs and how to treat them. The pulmonary hypertension problem has also not been resolved, and we need to determine how to treat and monitor bone disease. In addition, the future role of substrate deprivation needs to be determined, and further research is required before gene therapy becomes a potential clinical option. The high cost of enzyme replacement treatment for Gaucher disease remains an important issue.