Biofilms are communal structures of microorganisms encased in an exopolymeric coat that form on both natural and abiotic surfaces and have been associated with a variety of persistent infections that respond poorly to conventional antibiotic chemotherapy. Biofilm infections of certain indwelling medical devices by common pathogens such as staphylococci are not only associated with increased morbidity and mortality but are also significant contributors to the emergence and dissemination of antibiotic resistance traits in the nosocomial setting. Current treatment paradigms for biofilm-associated infections of semipermanent indwelling devices typically involve surgical replacement of the device combined with long-term antibiotic therapy and incur high health care costs. This review summarizes the existing data relating to the nature, prevalence, and treatment of biofilm-associated infections and highlights experimental approaches and therapies that are being pursued toward more effective treatments.