Hirschsprung's disease is characterized by the absence of enteric neurons from the distal colon and rectum. We reviewed the history of Hirschsprung's disease from its first description till the experimental approaches of its pathogenesis today. In our laboratory we introduced the use of monoclonal antibodies directed against neurofilament epitopes as useful tools in the diagnosis of Hirschsprung's disease and allied disorders. One particular monoclonal antibody (2FII) enables to distinguish between classical Hirschsprung's disease, long segment aganglionosis, hypoganglionosis, hyperganglionosis and chronic constipation. We also used monoclonal antibodies in experimental studies concerning the formation and malformation of the enteric nervous system in murine and chicken embryos. One particular antibody (HNK-I) was found to be a marker for very early precursors of enteric neurons in chicken (and human) embryos. In chicken embryos HNK-I visualizes cephalic neural crest cells, the area in the embryo that gives rise to all neurons in the gut. Using a microsurgical technique, we developed a model for Hirschsprung's disease in the chicken embryo.