Treatment of bone and joint infections (BJIs) is a challenge since antibiotics must penetrate the rigid structure of bone and reach the synovial space. On one hand, pharmacokinetic (PK) profile, that is, antibiotic penetration into bone and joint tissues, is a key element for clinical success. On the other hand, the pharmacodynamic (PD) profile, which is the mechanism and the quickness of bactericidal activity, is also important since the timely choice of the molecule (or association between molecules) prevents the destruction of joints/bones and the loss of their function. Lastly, anti-biofilm activity, which is the capacity of any antibacterial molecule to penetrate and eradicate bacterial biofilm, is another key element in enhancing BJIs’ clinical outcome.