Clinically significant nephrotoxicity has been reported when penicillin-based antibiotics (specifically piperacillin-tazobactam and flucloxacillin) are used in combination with vancomycin. These two drug classes in combination have been the mainstay of therapy for infections suspected to be caused by staphylococci, or for other serious infections such as febrile neutropenia, sepsis, and skin and soft tissue infections. However, the risk of nephrotoxicity has introduced uncertainty around their use in clinical practice. Despite this preliminary research suggesting potential adverse effects from the combination, data defining the toxicological mechanism, risk factors (including duration of therapy), clinical and biochemical progression and patient outcomes are largely unavailable. The role of Staphylococcus aureus itself in causing renal toxicity in this setting remains unknown. Additionally, the safety of alternative regimens (eg cephalosporins in combination with vancomycin) has not been proven. This information is urgently needed to inform clinical practice.