The enteric nervous system (ENS) in our gastrointestinal tract, nicknamed the ``second brain'', is responsible for normal gut function and peristaltic contraction. Embryonic development of the ENS involves the colonization of the gut wall from one end to the other by a population of proliferating neural crest cells. Failure of these cells to invade the whole gut results in the relatively common, potentially fatal condition known as Hirschsprung disease. We have collaborated with developmental biologists for over ten years, addressing various aspects of ENS development and disease. Both continuum and discrete models have provided insight into the key biological processes required for complete colonization and have generated experimentally testable predictions.