Lysosomal storage diseases (LSDs), which are inborn errors of metabolism, encompass around 50 different inherited syndromes. Together, they have an incidence of 1/7000 newborns. LSDs are caused by deficiencies in lysosomal enzymes or transporters, resulting in intra-lysosomal buildup of under graded metabolites. Common features of LSDs include bone disease, organomegaly and central and peripheral nervous system degeneration. These diseases were first described in the 1880s. Despite more than an hundred years of study of the genetic and molecular bases of LSDs, little is known about the events that lead from intra-lysosomal accumulation to the distinctive cell dysfunction and pathology that is characteristic of each disease. This review focuses on the main historical discoveries in LSD biology, from the original descriptions of their phenotypes, to animal models, including therapeutic strategies and challenges to treat this family of devastating diseases.