The human gastrointestinal (GI) tract harbors eukaryotic and prokaryotic viruses and their genomes, metabolites, and proteins, collectively known as the “gut virome”. This complex community of viruses colonizing the enteric mucosa is pivotal in regulating host immunity. The mechanisms involved in cross communication between mucosal immunity and the gut virome, as well as their relationship in health and disease, remain largely unknown. Herein, we review the literature on the human gut virome’s composition and evolution and the interplay between the gut virome and enteric mucosal immunity and their molecular mechanisms. Our review suggests that future research efforts should focus on unraveling the mechanisms of gut viruses in human homeostasis and pathophysiology and on developing virus-prompted precision therapies.