Patients cared for in the intensive care unit (ICU) undergo multiple interventions to treat serious medical conditions. In addition to the acute illness being treated, underlying chronic conditions require ongoing drug therapy. As a result, these patients are exposed to numerous pharmaceutical agents, many of which have narrow therapeutic windows and toxic potential. Comorbid conditions, altered drug pharmacokinetics, and drug-drug interactions further enhance the risk for both drug overdosing and underdosing and adverse medication effects. Underdosing is complicated by reduced efficacy, whereas overdosing results in various end-organ toxicities. One such complication is acute kidney injury (AKI), a relatively common problem in the ICU, which results from multiple insults. Importantly, potentially nephrotoxic medications contribute significantly to the development of AKI. In view of these issues, it is crucial that clinicians caring for these patients use appropriate drug dosing based on the knowledge of altered pharmacokinetics, vigilant monitoring of drug efficacy and toxicity, recognition of drugs with nephrotoxic potential, and early identification of drug-induced AKI when it develops.