Resistance to current therapeutic interventions is a major challenge in the treatment of patients affected by cancer. While nitric oxide (NO) might have proneoplastic properties, it is now clear that at high doses, NO has a role in cancer therapeutics. Either as a single agent or in combination with other antineoplastic compounds, NO might be used to overcome tumor cell resistance to conventional treatments. The following discussion addresses the role of NO in cancer therapeutics and includes a report on the role of NO donors in the area of cancer therapeutics.