Two epidemic, phylogenetically distant lineages of Clostridium difficile recently emerged and have been linked to increased virulence and mortality. Collins et al. show that two epidemic ribotypes (RT027 and RT078) have acquired the ability to metabolize low concentrations of the disaccharide trehalose. RT027 contains a single point mutation in the trehalose repressor that increases its sensitivity to trehalose and leads to the expression of the TreA enzyme, which is involved in trehalose metabolism. The data indicate that increased disease severity of RT027 is possibly due to increased toxin production. RT078 acquired four genes involved in trehalose metabolism, including a trehalose transporter that is necessary and sufficient for growth on low concentrations of trehalose and confers a competitive advantage over other lineages in the presence of trehalose. The authors propose that the use of trehalose in the human diet had a role in the emergence of these epidemic and hypervirulent strains.