Despite it was initially used and was restricted mainly for the treatment of tuberculosis, rifampicin gained in past years interest for the treatment of infections associated with prosthetic devices. Rifampicin has an excellent tissue penetration and a unique activity on bacteria in biofilms growing on the surface of prosthetic devices. The rapid emergence of resistance in bacteria constitutes the Achilles' heel and therefore rifampicin should be used with caution. This review addresses the mode of action of rifampicin and describes possible pitfalls of its use.