The concept of" lysosomal storage disorders" was introduced by Hers in 1965 (1) to explain how genetically determined absence of a seemingly unimportant enzyme, a-glucosidase, could lead to the fatal condition known as Pompe disease. The undegraded substrate would gradually accumulate within lyso somes, causing progressive increase in the size and number of these organelles; the cellular pathology would eventually lead to malfunction of the affected organ. This concept quickly led to the discovery of additional lysosomal storage disorders, which at this time number three dozen (Table 1). The majority are caused by deficiency of a single lysosomal enzyme; others, for which I-cell disease is the paradigm, result from pleiotropic loss of several lysosomal enzymes because of an underlying defect in some common protein. Although the total number of known lysosomal storage diseases has not changed much since the subject was last reviewed in this series (2), research activity in the field has been intense in the intervening years. The 1989 edition of The Metabolic Basis of Inherited Disease (3) devotes 300 pages, documented by more than 3500 references, to the topic. The reader is directed in Table 1 to chapters in this compendium and other reviews for detailed accounts of the clinical, pathological, biochemical, genetic, and molecular aspects of individual disorders or classes of related disorders (4-20). The current review concentrates on recent developments in the area of lysosomal cnzyme deficiency diseases, and focuses on general issues such as processing of normal and mutant enzymes, the structure of normal and mutant genes, correlation of genotype with phenotype, and development of therapeutic strategies. The interesting areas of transport of small molecules out of lyso somes and genetic defects thereof (20, 20a) are not in the purview of this chapter.