The early recognition of ifosfamide-related renal dysfunction, including arginine vasopressin resistance (previously referred to as diabetes insipidus), which is characterized by polyuria due to the inability of the collecting duct to concentrate urine, as well as direct proximal tubular injury, which is characterized by numerous metabolic disturbances including hypophosphatemia, metabolic acidosis, hypokalemia, and glucosuria, is paramount to timely initiation of treatment and titration of desmopressin. In this report, we present a case of a 42-year-old female with a history of spindle cell carcinoma of the left thigh, who was referred to the inpatient nephrology consult service for acute kidney injury, polyuria, and metabolic derangements following her sixth cycle of doxorubicin-ifosfamide chemotherapy. The patient was treated with supratherapeutic doses of desmopressin, with successful improvement of her polyuria. We review the pathophysiology of different forms of ifosfamide-associated nephrotoxicity, including arginine vasopressin resistance, the challenges of diagnosing arginine vasopressin disorders, and the utility of desmopressin in the management of arginine vasopressin resistance. This case also highlights the clinical implications of using copeptin in the diagnosis of arginine vasopressin resistance, leading to effective treatment and improving patient outcomes.