Krabbe disease is caused by genetic defects in the lysosomal enzyme galactocerebrosidase (GALC) (1). Although its overall prevalence is 1:100,000 births in the general population, the frequency of Krabbe disease is as high as 1:150 in certain communities. Also called globoid-cell leukodystrophy, the resultant accumulation of psychosine, a toxic metabolite derived from galactocerebroside, leads to the death of cells forming the myelin sheath of the nervous system. Devastatingly, the majority of patients are infants diagnosed within 6 mo, and rapid disease progression results in death within 2 y (2), although patients with later onset who develop neurological symptoms in their 50’s are also known (3). Newborn screening for such inborn errors of metabolism is conducted in the United States and throughout the world but has little to offer parents who receive a positive Krabbe disease diagnosis for their infant (4). Our understanding of the pathophysiology of Krabbe disease is very limited, and the available treatment, hematopoietic stem cell transplantation (5), must be conducted early and has had mixed results (4, 6). In this issue of PNAS, Deane et al. (7) report the first crystal structure of GALC [from Mus musculus, 83% identity with human enzyme and member of the GH59 family of carbohydrate activating enzymes (CAZy database, www.cazy.org) (8)], narrowing the gulf between the genetic causes of Krabbe disease and its clinical manifestations. The structure with and without galactose bound reveals a surprising architecture for glycoside hydrolases, confirms active site residues and aspects of catalysis, and provides critical insights …