Innovations in DNA sequencing and biocomputing have enabled thorough characterization of the diverse collection of microorganisms that inhabit the human body (i.e., the human microbiome). Recent studies of the human microbiome have implicated its involvement in myriad human diseases, and suggest that the microbiome may serve as a clinically relevant diagnostic or therapeutic target. The bioinformatic methods used to analyze microbiome sequence data, which is unusually voluminous and complex, are still in their infancy and are rapidly evolving. Here, I discuss several of the recent computational and statistical approaches we have developed to analyze microbiome sequence data with the goal of improving the discovery of diagnostics and microbiome-mediated disease mechanisms. I also discuss our efforts to use these methods to characterize the microbiome's involvement in the development of inflammatory bowel disease.