The pathogenesis of device-associated infections is related to biofilm bacteria that exhibit distinct characteristics with respect to growth rate, structural features, and protection from host immune mechanisms and antimicrobial agents when compared with planktonic counterparts. Biofilm-associated infections are prevented, diagnosed, and treated differently from infections not associated with biofilms. This article reviews innovative concepts for the prevention of biofilm formation, and novel treatment approaches. Specific approaches for the diagnosis and prevention of catheter-associated urinary tract and bloodstream infections, as well as infections associated with orthopedic implants and cardiovascular implantable electronic devices, are also discussed.