The role of nitric oxide (NO()) as a mediator of cancer phenotype has led researchers to investigate strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain. Unfortunately, NO() serves multiple functions in cancer physiology. In some instances, NO() or nitric oxide synthase (NOS) levels correlate with tumor suppression and in other cases they are related to tumor progression and metastasis. Understanding this dichotomy has been a great challenge for researchers working in the field of NO() and cancer therapy. Due to the unique chemical and biochemical properties of NO(), it's interactions with cellular targets and the subsequent downstream signaling events can be vastly different based upon tumor heterogeneity and microenvironment. Simple explanations for the vast range of NO-correlated behaviors will continue to produce conflicting information about the relevance of NO() and cancer. Paying considerable attention to the chemical properties of NO() and the methodologies being used will remove many of the discrepancies in the field and allow for in depth understanding of when NO-based chemotherapeutics will have beneficial outcomes.