A team approach among orthopaedic surgeons, infectious disease specialists, and patients is of paramount importance when treating periprosthetic joint infections (PJIs). Treatment usually includes various surgical approaches along with antibiotic treatment. Antibiotic selection requires a multifactorial decision that depends on the organism that is identified, its antibiotic-resistance profile, the extent of the infection, and factors associated with the host. Antibiotic duration is dependent on surgical intervention and the type of organism. Typically, patients are treated for 6 weeks after debridement, antibiotics, and implant retention (DAIR) and for 4 to 6 weeks after single-stage and 2-stage revision arthroplasty. Levofloxacin in combination with rifampin has shown favorable outcomes for Staphylococcus PJI treatment. Quinolones have excellent bioavailability and bone and joint concentrations. Ciprofloxacin can be used for sensitive gram-negative infections. Evidence is emerging that supports the use of oral antibiotics after 7 days of intravenous antibiotics for the treatment of PJI. Although this should be considered carefully, it can potentially alleviate the burden on patients and caregivers, with fewer intravenous lines and the potential for fewer complications.