The demand for joint replacement surgery is continuously increasing with rising costs for hospitals and healthcare systems. Staphylococci are the most prevalent etiological agents of orthopedic infections. After an initial adhesin-mediated implant colonization, Staphylococcus aureus and Staphylococcus epidermidis produce biofilm. Biofilm formation proceeds as a four-step process: (1) initial attachment of bacterial cells; (2) cell aggregation and accumulation in multiple cell layers; (3) biofilm maturation and (4) detachment of cells from the biofilm into a planktonic state to initiate a new cycle of biofilm formation elsewhere. The encasing of bacteria in biofilms gives rise to insuperable difficulties not only in the treatment of the infection, but also in assessing the state and the nature of the infection using traditional cultural methods. Therefore, DNA-based molecular methods have been developed to provide rapid identification of all microbial pathogens. To combat biofilm-centered implant infections, new strategies are being developed, among which anti-infective or infective-resistant materials are at the forefront. Infection-resistant materials can be based on different approaches: (i) modifying the biomaterial surface to give anti-adhesive properties, (ii) doping the material with antimicrobial substances, (iii) combining anti-adhesive and antimicrobial effects in the same coating, (iv) designing materials able to oppose biofilm formation and support bone repair.