The human enteric nervous system (ENS) is derived from the neural crest and represents a complex network of ~500 million neurons with dozens of distinct neurotransmitter and hormone subtypes essential for gastro-intestinal (GI) activities. Despite the significance of the human ENS and its involvement in a wide range of GI disorder, there is very little known about its biology due to the lack of accessible tissue. Directed differentiation of human pluripotent stem cells (hPSCs) offers and alternative approach for the derivation of distinct, functional cell types that can be utilized in a broad range of basic and translational applications. We have recently succeeded in derivation of the ENS lineages from hPSCs and applied them for cell therapy and drug discovery in Hirschsprung disease, which is the most common developmental disorder of the ENS. These studies set the stage for future investigations of the human ENS biology and a better understanding of disease mechanisms and advancement of therapeutic interventions for enteric neuropathies.