Iatrogenic hypoglycemia is the main factor limiting aggressive and optimal diabetes management. Rather than being an inevitable consequence of optimal glycemic control, however, hypoglycemia is avoidable and generally straightforward to manage when it occurs. Professional caregivers, patients, and their families are often fearful of hypoglycemia, even though most episodes are minor and easily self-treated. Understanding the factors contributing to hypoglycemia risk and how to minimize its occurrence is an essential part of diabetes care. Building on the physiologic fundamentals presented in the accompanying review, the incidence, mortality/morbidity, clinical symptoms, severity classification, and psychosocial impact of hypoglycemia are described here. Appropriate selection and titration of therapeutic agents, including insulin analogs with more predictable time-action profiles than human insulin formulations, can reduce hypoglycemia risk. Patient education about hypoglycemia prevention, including symptom recognition and necessity of rapid treatment, behavioral modification, and the importance of frequent blood glucose monitoring should accompany all therapeutic interventions.