Clostridioides difficile causes >500,000 infections, >30,000 deaths, and > $5 billion/year in US healthcare costs, and rates continue to rise. Antimicrobial therapy that ablates the commensal microbiota commonly triggers infection, allowing the pathogen to proliferate and release toxins that damage host mucosal surfaces. Resistance to commonly prescribed antibiotics occurs in >20% of patient isolates, a problem that confounds treatment and increases risks for recurrent infections. In this research program, we are building predictive and mechanistic models to define mechanisms by which C. difficile responds to antibiotics, host and microbiota-origin factors, and to develop therapeutic interventions to prevent colonization, infection and recurrence of C. difficile.