Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to reduced oxygen availability. The HIF-1β subunit is constitutively expressed, whereas the HIF-1α subunit is subject to ubiquitination and proteasomal degradation, a process that is inhibited under hypoxic conditions. Recent data indicate that HIF-1 plays major roles in the prevention of myocardial and cerebral ischemia and in the pathogenesis of pulmonary hypertension and cancer. Modulation of HIF-1 activity by genetic or pharmacological means could provide a novel therapeutic approach to these common causes of mortality.