A new challenge to overcoming tumor resistance to conventional treatment is represented by the development of novel nitric oxide (NO) donors. It is now clear that while low doses of NO have proneoplastic properties, high doses exert antitumor/antiangiogenic activities through multiple mechanisms. This review focuses on the role of exogenous NO in cancer therapy and reports the state of the art regarding different NO-donating agents in cancer treatment, particularly in relation to angiogenesis inhibition.