Staphylococcus aureus is an important human pathogen that causes a wide range of infectious conditions both in nosocomial and community settings. Biofilms serve to protect S. aureus from host defenses and antimicrobial agents and therefore play a role in Staphylococcus host pathogenesis. Indeed, biofilm-dwelling bacteria are generally able to tolerate much higher concentrations of antimicrobials than their planktonic counterparts. As a result, biofilm-associated infections are notoriously difficult to eradicate. There is an urgent need for alternative approaches to treat biofilm-related infections. In this review, we present various strategies to combat biofilmrelated infections such as small molecules, enzyme therapy and vaccines that weaken structure of bacterial biofilm. However, these promising approaches remain to be validated clinically. Therefore, it is anticipated that these approaches will be eventually developed for treatment of problematic biofilm-related infections notably those are caused by S. aureus.