The historic town of Taos, New Mexico, with its rich multicultural history of art and craft, was the site of the second Keystone Symposium on 'Endoderm Development and Disease', which was held in February 2018. The theme of the meeting was 'Cross-Organ Comparison and Interplay', emphasizing an integrative and multisystem approach to the broad topics of organ physiology, homeostasis, repair, regeneration and disease. As we review here, participants shared their recent discoveries and discussed how new technologies developed in one organ system might be applied to answer crucial questions in another. Other integrative themes were how agents such as parasites, microbes, immune cells, physical forces and innervation can affect tissue organization and progenitor cell dynamics, and how defects in the development of an organ can impact its adult function. Participants came away with a broader vision of their field and a renewed sense of collective energy empowered by novel tools and fresh ideas.