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"I-Cell disease" (ICD) has received its name because of the innumerable intracytoplasmatic inclusions in connective tissue cells and in vitro fibroblasts derived from patients. It is a progressive disorder already recognizable in infancy. Severe disturbance of growth, coarsening facial features and moderate to severe psychomotor handicap are the most important clinical characteristics. ICD is fatal already in childhood. Prominent among many anatomo- and physiopathologic abnormalities is the paradox of a very reduced activity of many lysosomal hydrolases in connective tissue cells on the one hand and the strongly enhanced activity of these hydrolases in body fluids and culture media on the other hand. Similar, albeit less pronounced abnormalities are observed also in patients with pseudo-Hurler polydystrophy, (PHP) a related though milder disorder. In patients with either ICZ or PHP, phosphorylation of oligomannosyl type sidechains in acid hydrolases, known to be glycoproteins, does not occur. Because the mannose-6-phosphate (M-6-P) recognition marker necessary for normal transport of nascent hydrolases to the lysosomal compartment is not formed, these enzymes are not retained in the cells. The underlying cause is a functionally deficient N-acetylglucosaminephosphotransferase in ICD and PHP patients. The pathological consequences of this defect are more pronounced in fibroblasts than in parenchymatous cells, because the former lack alternative mechanisms by which hydrolases can reach lysosomes. The number of known secondary abnormalities in ICD remain useful for confirmation of the clinical diagnosis and for prenatal diagnosis. The elucidation of the metabolic defect in ICD, a rare monogenic disorder, has increased considerably knowledge on enzyme maturation and on the physiology of intracytoplasmic organelles.