E2F family of transcription factors are best known for regulating genes involved in cell cycle control, cell proliferation, tumorigenesis, and apoptosis. Recent evidences have revealed their critical involvement in modulating cellular response to hypoxia and ischemia in a variety of physiological and pathological processes. Of particular interest are findings that E2Fs act as both regulators and targets of microRNAs that govern hypoxic/ischemic angiogenesis. This review focuses on the crosstalk between E2Fs and microRNAs that have been shown to participate in the regulation of angiogenesis, hypoxia response and ischemic disease.