Medical devices are responsible for a large portion of nosocomial infections, particularly in critically ill patients. Device-associated infections can cause major medical and economic sequelae. Bacterial colonization of the indwelling device can be a prelude to both infection and malfunction of the device. The pathogenesis of device-associated infection centers around the multifaceted interaction among the bacteria, the device, and the host. Bacterial factors are probably the most important in pathogenesis of infection, whereas device factors are the most amenable to modification with the objective of preventing infection. Some, but not all, of the studied bacterial receptors satisfy the proposed "adherence/infection" version of Koch's postulates. Traditional surface-modifying preventive approaches have largely focused on antimicrobial coating of devices and resulted in variable clinical success in preventing device-associated infections. The potential protective role of newer innovative approaches, such as biofilm modification and bacterial interference, ought to be further investigated.