Bacteria can grow by forming a matrix-enclosed biofilm which adheres to a surface, providing some major advantages over the planktonic form of the organism. The ability to colonize different surfaces is utilized by some bacterial species, leading to significant infections. These range from minor skin complaints to life-threatening systemic infections. Bacteria adhering to implanted medical devices may be the cause of recurrent infection; bacterial persistence and the increasing use of indwelling medical devices has led to a steady increase in device-related bacterial infections. These bacteria are very resistant to antimicrobial therapy and the concentration of drugs required to achieve bactericidal activity may be at a higher order of magnitude than for planktonic bacteria. Different control strategies have been designed to inhibit biofilm formation on medical devices; however, it seems that biomaterial composition may play a role in the development of antimicrobial resistance, depending on the composition of the biomaterial, the bacterial species and the drugs. In this review, we discuss the most important mechanisms related to biofilm resistance to antimicrobial agents and bacterial interaction with medical devices, and their consequences for treatment failure.