The gastrointestinal (GI) tract harbors a diverse and host-specific gut microbial community. Whereas host-microbe interactions are based on homeostasis and mutualism, the microbiome also contributes to disease development. In this review, we summarize recent findings connecting the GI microbiome with GI disease. Starting with a description of biochemical factors shaping microbial compositions in each gut segment along the longitudinal axis, improved histological techniques enabling high resolution visualization of the spatial microbiome structure are highlighted. Subsequently, inflammatory and neoplastic diseases of the esophagus, stomach, and small and large intestines are discussed and the respective changes in microbiome compositions summarized. Finally, approaches aiming to restore disturbed microbiome compositions thereby promoting health are discussed.