The determinants of drug utilization are complex and multifactorial, and understanding how, why, when and where drugs are used is crucial to inform regulatory and payment policy and clinical practice. We begin by reviewing methods of investigating drug utilization and evaluating interventions to prescribing. We then explore common challenges to optimizing medicine use, including non-adherence and off-label drug use. We also consider methods to improve the quality of drug utilization, including value-based insurance designs, audit and feedback, patient education and medication therapy management. We also consider varied patient, provider, practice and system-level determinants of prescription drug utilization, including marketing and promotion, emerging evidence of benefits and harms, regulation and changes in coverage and reimbursement. Finally, we use four case studies to reinforce many of the core topics we’ve explored: antibiotics, prescription opioids, anticoagulants and generics and biosimilars.