The mechanisms by which tumors recruit their vasculature has been subject to intense investigations. The acquisition of a functional blood supply seems to be rate-limiting for the ability of a tumor to grow beyond a certain size and to metastasize to other sites. Accumulating evidence indicates that hypoxia and the key transcriptional system, HIF (hypoxia-inducible factor), are the major triggers for new blood vessel growth in malignant tumors. Although vessel growth and maturation are complex and highly coordinated processes requiring the sequential activation of a multitude of factors, there is a consensus that vascular endothelial growth factor and angiopoietin signaling represent crucial steps in tumor angiogenesis. Recent insights into cellular and molecular crosstalk suggest a model in which hypoxia, HIF, and several HIF target genes participate in the coordinated collaboration between tumor, endothelial, inflammatory/hematopoietic, and circulating endothelial precursor cells to enhance and promote tumor vascularization. A well-integrated understanding of this intricate microenvironment may offer new opportunities for therapeutic intervention.