Staphylococcus epidermidis and Staphylococcus aureus are common causes of biofilm-mediated prosthetic device-related infection. The polysaccharide adhesion mechanism encoded by the ica operon is currently the best understood mediator of biofilm development, and represents an important virulence determinant. More recently, the contributions of other virulence regulators, including the global regulators agr, sarA and σB, to the biofilm phenotype have also been investigated. Nevertheless, little has changed at the bedside; the clinical and laboratory diagnosis of device-related infection can be difficult, and biofilm resistance frequently results in failure of therapy. This review assesses the way in which advances in the understanding of biofilm genetics may impact on the clinical management of device-related infection.