The recent understanding that hydrophobic β-lactams have greater affinity for organic anion transporter-3 (OAT-3) of the proximal renal tubule could provide valuable insights for anticipating β-lactams that may exacerbate vancomycin-induced nephrotoxicity. Vancomycin alone provides oxidative stress on the highly metabolic proximal tubular cells. Hydrophobic β-lactams (eg, piperacillin and anti-staphylococcal β-lactams) could have greater OAT-3 mediated uptake into proximal tubular cells than hydrophilic β-lactams (eg, most cephalosporins and carbapenems), thereby causing greater mitochondrial stress on these susceptible cells. It remains to be seen whether concomitant drugs that inhibit OAT-3 mediated cellular uptake of β-lactams into proximal tubular cells or provide antioxidant effects might mitigate β-lactam augmented vancomycin nephrotoxicity. Furthermore, the serum creatinine rise seen with vancomycin and hydrophobic β-lactams might represent competition for creatinine-secreting transporters (of which OAT-3 is one), thus, indicating creatinine retention rather than renal injury. In the meantime, clinicians are advised to utilise less nephrotoxic combinations in both empirical and directed antibiotic selection settings until further research is conducted.