Protein S-nitrosylation (SNO), emerging as an important posttranslational modification, involves covalent addition of nitric oxide (NO) to the sulfur atom of cysteine in proteins. Accumulated evidence suggests that protein SNO plays crucial roles in pathophysiological mechanisms in cancer, which is attracting great attention. However, there are still controversies about whether S-nitrosylated proteins act as oncogenic proteins or tumor suppressors in cancer. In this review, we provide an overview of the early and latest evidence regarding the underlying mechanism and dual roles of SNO in cancer, in an effort to clarify its contribution in tumor progression. It has been well established that S-nitrosylated proteins restrain tumor progression in several types of cancer, while they have exhibited activities in promoting cell proliferation and inhibiting apoptosis in some other kinds of cancer. Interestingly, emerging evidence also has highlighted both its anti-cancer and pro-tumorigenic roles in several other cancer diseases. Finally, current limitations and future research prospects are presented. The overview of targeting SNO in cancer will provide new opportunities for drug development through in-depth exploration of SNO-mediated signaling pathways.