The bacterium Vibrio cholerae is the etiologic agent of the severe human diarrheal disease cholera. The gut microbiome, or the native community of microorganisms found in the human gastrointestinal tract, is increasingly being recognized as a factor in driving susceptibility to infection, in vivo fitness, and host interactions of this pathogen. Here, we review a subset of the emerging studies in how gut microbiome structure and microbial function are able to drive V. cholerae virulence gene regulation, metabolism, and modulate host immune responses to cholera infection and vaccination. Improved mechanistic understanding of commensal-pathogen interactions offers new perspectives in the design of prophylactic and therapeutic approaches for cholera control.