Abstract Vancomycin and piperacillin-tazobactam are 2 of the most commonly prescribed antibiotics in hospitals. Recent data from multiple meta-analyses suggest that the combination increases the risk for vancomycin-induced kidney injury when compared to alternative viable options. However, these studies are unable to prove biologic plausibility and causality as randomized controlled trials have not been performed. Furthermore, these studies define acute kidney injury according to thresholds of serum creatinine rise. Serum creatinine is not a direct indicator of renal injury, rather a surrogate of glomerular function. More reliable, specific, and sensitive biomarkers are needed to truly define if there is a causal relationship with increased toxicity when piperacillin-tazobactam is added to vancomycin. This viewpoint will explore the available evidence for and against increased acute kidney injury in the setting of vancomycin and piperacillin-tazobactam coadministration.