Prolonged ischemic insult can cause irreversible tissue injuries. Despite advances in medical and surgical therapies, myocardial infarction and stroke, both consequences of ischemic insults, remain to be the top two causes of morbidity and mortality in the Western world, with survivals usually carrying permanent disabilities. Treatments that help restoring blood flow to ischemic area remain to be one of the most important therapeutic goals. Enhancing the innate angiogenesis by exogenous delivery of angiogenic factors lessens the ischemic injury. However, uncontrolled angiogenic gene expression can cause some unwanted side effects. In this mini-review, we describe two systems that can be used to mediate hypoxia-inducible and tissue-specific gene expression.