Staphylococcus spp. causes more than half of all osteoarticular infections of native structures or implanted material. The ability of Staphylococcus spp. to persist within infected bone tissue and to produce a bacterial biofilm, most notably in infections of implanted material, can lead to treatment failures and microbiological relapses. Rifampin is a cornerstone of the treatment of staphylococcal osteoarticular infections, particularly those of implanted material. Rifampin is a bactericidal antibiotic that diffuses very well within bone tissue and bacterial biofilms. The mechanism of action is inhibition of bacterial DNA transcription to mRNA independently from bacterial division, which results in activity against even dormant Staphylococcus spp. organisms. However, the high risk of emergence of rifampin-resistant mutants requires the concomitant administration of another antibiotic. Several antibiotics are recommended in the French guidelines issued by the French-Speaking Society for Infectious Diseases (Société de Pathologie Infectieuse de Langue Française [SPILF]). Here, we discuss the results from in vitro, animal, and clinical studies that explain the advantages and drawbacks of each antibiotic used with rifampin to treat osteoarticular infections due to Staphylococcus spp.