Human single gene disorders that affect the nervous system provide a host of natural mutations that can be deployed in the quest to understand its development and function. A paradigm for this approach is the study of disorders caused by mutations in the gene for the neural cell recognition molecule L1. L1 is the founder member of a subfamily of cell adhesion molecules that are primarily expressed in the nervous system, and to date it is the only one to be associated with a hereditary disease. In this review we will summarize how the analysis of pathological mutations in L1 is complementing the study of mouse models and in vitro analysis of L1 function.