Gangliosides are expressed on all vertebrate cells and tissues, but are particularly abundant in the mammalian brain, where they constitute major cell-surface determinants on all nerve cells. The same four ganglioside structures, GM1, GD1a, GD1b, and GT1b, constitute the great majority of brain gangliosides in all mammals. Biosynthesis of these major brain gangliosides starts with addition of glucose to the ceramide lipid carrier followed by stepwise addition of up to six additional monosaccharides. This primarily involves the sequential action of seven glycosyltransferases, many of which appear to act specifically on glycolipid (rather than glycoprotein) acceptors. Congenital human disorders of ganglioside biosynthesis are exceedingly rare, but provide a glimpse into the functions of these major nerve cell surface components. To date, less than 100 individuals from 36 family pedigrees have been confirmed to carry deleterious mutations in ganglioside biosynthetic genes. Mutations in ST3GAL5 (coding GM3 synthase) were discovered as the basis for severe congenital infantile seizures, whereas mutations in B4GALNT1 (coding GM2/GD2 synthase) are the basis of hereditary spastic paraplegia accompanied by intellectual disability. In this review, we compile and summarize the findings of these studies, compare human disorders with mouse genetic models, and reflect on the implications for understanding ganglioside function and dysfunction in the nervous system.