Analysis of the esophageal microbiome remains a new field of research. Two hypothesis-generating papers published in the current issue of the Journal go beyond characterizing the esophageal microbiome in Barrett's esophagus or eosinophilic esophagitis (EoE). Snider et al. suggest that the salivary microbiome can be used as a screening tool for Barrett's esophagus, and Arias et al. demonstrates abnormal expression of Toll-like receptors and innate immune effector proteins in patients with active EoE. We discuss these findings, raise fundamental questions about microbiome studies, and offer ideas for future studies.