The nitric oxide (NO) and 3’,5’-cyclic guanosine monophosphate (cGMP) pathway is one of the best characterized signalling cascades that plays a central role in several physiological processes such as vasodilation, neurotransmission, and embryonic development. Soluble guanylyl cyclase (sGC) is the key receptor for NO with α1β1 as predominate heterodimer for the function. Nitric oxide binds to the ferrous heme at histidine 105 of the β1 subunit and leads to at least a 200-fold increase in sGC activity and cGMP production . On the other hand, the effects of NO can be attributed to cGMP-independent pathway which is mainly mediated by reactive oxygen/nitrogen species such as highly reactive peroxynitrite (ONOO-) . The role of NO and cGMP signalling in tumour biology has been extensively studied during the past three decades, however a consensus regarding the precise role that the NO/cGMP signalling axis plays in neoplastic transformation has not been reached. Simple applications of NO or cGMP regulating reagents to various cancer cell lines or animal models has generated controversial results. We suggest several factors are contributing to this ambiguity: First, although the NO participates in normal signalling (e.g., vasodilatation and neurotransmission), NO is also a cytotoxic or apoptotic molecule when produced at high concentrations by inducible nitric oxide synthase (iNOS or NOS-2). Also, the cGMP-dependent (NO/sGC/cGMP pathway) and cGMP-independent (NO/oxidative pathway) components may vary among different tissues and cell types. Furthermore, solid tumours contain two compartments: the parenchyma (neoplastic cells) and the stroma (nonmalignant supporting tissues including connective tissue, blood vessels, and, inflammatory cells) with differing NO biology. Therefore, the NO/sGC/cGMP signalling molecules in tumours as well as the surrounding tissue must be further characterized before targeting this signalling pathway for tumour therapy.