Bacterial biofilms are very resistant to antimicrobial activity. The concentration of drugs required to achieve bactericidal activity may be several orders of magnitude higher than the sensitivity for planktonic bacteria, since it is very difficult to completely sterilize infected surfaces. Biofilm antimicrobial resistance is a multifactorial process and is mainly related to the structural and physiological characteristics of the biofilms. Various control strategies have been designed to inhibit biofilm formation on medical devices, in most cases with little success. The most important mechanisms of biofilm resistance to antimicrobial agents and their effect on the activity of the main groups of antimicrobials are discussed.