Alpha-mannosidosis in the human is an autosomal recessive lysosomal storage disease caused by a deficiency of lysosomal alpha-D-mannosidasea activity. Lysosomal alpha-D-mannosidase is involved in the catabolism of N-linked glycoproteins through the sequential degradation of high-mannose, hybrid and complex oligosaccharides. This review is focused on human, mouse, bovine and feline genes coding for lysosomal alpha-D-mannosidase. In particular the exon-intron structure of the genes, their promoters, and the identification of mutations causing the disease have been examined. The construction, by homologous recombination, of a mouse model of alpha-mannosidosis is reported.