The last decade has witnessed an unprecedented expansion in the design, synthesis and preclinical applications of various multifunctional nanomaterials. Efficient targeting of these nanomaterials to the tumor site is critical for delivering sufficient amount of anti-cancer drugs to suppress tumor growth, while avoiding undesired side effects. Although some nanoparticles could accumulate in the tumor tissue based on the enhanced permeability and retention effect, which may also bind to targets on the tumor cell surface after extravasation from the tumor vasculature, these strategies have many limitations. In this article, we discuss the concept of tumor vasculature targeting and summarize representative examples of in vivo targeted positron emission tomography imaging of various functionalized nanomaterials with different morphology, size and surface chemistry. The concept of targeting tumor vasculature instead of (or in addition to) tumor cells will continue to inspire the design of more advanced nanosystems for efficacious and personalized treatment of cancer in the future.