Drugs are a common source of acute kidney injury. Compared with 30 years ago, the average patient today is older, has more comorbidities, and is exposed to more diagnostic and therapeutic procedures with the potential to harm kidney function. Drugs shown to cause nephrotoxicity exert their toxic effects by one or more common pathogenic mechanisms. Drug-induced nephrotoxicity tends to be more common among certain patients and in specific clinical situations. Therefore, successful prevention requires knowledge of pathogenic mechanisms of renal injury, patient-related risk factors, drug-related risk factors, and preemptive measures, coupled with vigilance and early intervention. Some patient-related risk factors for drug-induced nephrotoxicity are age older than 60 years, underlying renal insufficiency (e.g., glomerular filtration rate of less than 60 mL per minute per 1.73 m2), volume depletion, diabetes, heart failure, and sepsis. General preventive measures include using alternative non-nephrotoxic drugs whenever possible; correcting risk factors, if possible; assessing baseline renal function before initiation of therapy, followed by adjusting the dosage; monitoring renal function and vital signs during therapy; and avoiding nephrotoxic drug combinations.