The free radical nitric oxide (NO center dot) is known to play a dual role in human physiology and pathophysiology. At low levels, NO center dot can protect cells; however, at higher levels, NO center dot is a known cytotoxin, having been implicated in tumor angiogenesis and progression. While the majority of research devoted to understanding the role of NO center dot in cancer has to date been tissue-specific, we herein review underlying commonalities of NO center dot which may well exist among tumors arising from a variety of different sites. We also discuss the role of NO center dot in human physiology and pathophysiology, including the very important relationship between NO center dot and the glutathione-transferases, a class of protective enzymes involved in cellular protection. The emerging role of NO center dot in three main areas of epigenetics-DNA methylation, microRNAs, and histone modifications-is then discussed. Finally, we describe the recent development of a model cell line system in which human tumor cell lines were adapted to high NO center dot (HNO) levels. We anticipate that these HNO cell lines will serve as a useful tool in the ongoing efforts to better understand the role of NO center dot in cancer.