Angiogenesis has been linked to cancer for eons. It is involved as an underlying process in the conversion of benign tumour to metastatic tumour stimulates angiogenesis by releasing various angiogenic factors, and has significant importance in the management of endothelial cell proliferation, migration, survival, cell–matrix and cell–cell adhesion via discrete intracellular signalling pathways that are considered to be the underlying mechanisms in tumour-driven angiogenesis. Multiple research investigations have shown that nitric oxide (NO) may encourage and prevent the growth and spread of tumours. Cellular sensitivity in response to NO, its exposure period and concentration and the activity of different NOS isoforms along with their localization appear to influence NO’s actions in malignancies. In this mechanism, nitric oxide synthase (NOS) performs a dual role, with low levels stimulating angiogenesis and high levels inhibiting it, acting as a labyrinth in tumour growth. This chapter delves into the intricate role of nitric oxide synthase (NOS) in tumour-driven angiogenesis, a vital step in cancer progression.