Hypophosphatemia (serum phosphorus concentration <2.5 mg/dl, 0.8 mmol/l), although rare in the general population, is commonly observed in hospitalized patients and may be associated with drug therapy. In fact, hypophosphatemia frequently develops in the course of treatment with drugs used in every-day clinical practice including diuretics and bisphosphonates. Proper diagnostic approach of patients with low serum phosphorus concentrations should involve a detailed medical history with special attention to the recent use of medications. The clinical manifestations of drug-induced hypophosphatemia are usually mild but might also be severe and potentially life-threatening. This review aims at a thorough understanding of the underlying pathophysiological mechanisms and risk factors of drug therapy-related hypophosphatemia thus allowing prevention and effective intervention strategies.