This review discusses the significance of nitric oxide (NO) signaling in the cardiovascular system, highlighting recent advances and unresolved questions. NO, produced by endothelial nitric oxide synthase (eNOS), plays a crucial role in vascular homeostasis, regulating blood flow, inhibiting platelet aggregation, and modulating vascular remodeling. The discovery of NO as an endogenous signaling molecule has led to extensive research on its physiological and pathological roles. However, dysregulation of NO signaling can contribute to cardiovascular diseases such as hypertension, coronary heart disease, and heart failure. The review covers both classical and non-classical pathways of NO generation, including the nitrate-nitrite-NO pathway, which involves the reduction of inorganic nitrate and nitrite to NO by various enzymes and non-enzymatic processes. This pathway is particularly important in conditions with low oxygen tension and acidemia, where the activity of the NOS system is reduced. Key aspects of NO signaling include the activation of soluble guanylyl cyclase (sGC) by NO, leading to cyclic guanosine monophosphate (cGMP) synthesis and downstream signaling through protein kinases and ion channels. NO can also be converted to higher nitrogen oxides, such as nitrate and nitrite, which can act as scavengers or form reactive species like peroxynitrite. The review explores the role of NO in cardiovascular health, emphasizing its importance in regulating tissue blood flow, vascular remodeling, and protecting the endothelium. In cardiovascular disease, dysregulation of NO signaling is implicated in various conditions, including hypertension, coronary heart disease, and heart failure. The review discusses pharmacological and non-pharmacological strategies aimed at increasing NO production or signaling, such as inhaled NO, organic nitrates, phosphodiesterase type 5 (PDE5) inhibitors, and sGC activators. Finally, the review highlights the potential of NO-Ferroheme as a signaling entity in the cardiovascular system, suggesting new avenues for therapeutic intervention. Despite the extensive research, questions remain about the chemical nature of NOS-derived bioactivity and the precise mechanisms of NO signaling in complex physiological processes.This review discusses the significance of nitric oxide (NO) signaling in the cardiovascular system, highlighting recent advances and unresolved questions. NO, produced by endothelial nitric oxide synthase (eNOS), plays a crucial role in vascular homeostasis, regulating blood flow, inhibiting platelet aggregation, and modulating vascular remodeling. The discovery of NO as an endogenous signaling molecule has led to extensive research on its physiological and pathological roles. However, dysregulation of NO signaling can contribute to cardiovascular diseases such as hypertension, coronary heart disease, and heart failure. The review covers both classical and non-classical pathways of NO generation, including the nitrate-nitrite-NO pathway, which involves the reduction of inorganic nitrate and nitrite to NO by various enzymes and non-enzymatic processes. This pathway is particularly important in conditions with low oxygen tension and acidemia, where the activity of the NOS system is reduced. Key aspects of NO signaling include the activation of soluble guanylyl cyclase (sGC) by NO, leading to cyclic guanosine monophosphate (cGMP) synthesis and downstream signaling through protein kinases and ion channels. NO can also be converted to higher nitrogen oxides, such as nitrate and nitrite, which can act as scavengers or form reactive species like peroxynitrite. The review explores the role of NO in cardiovascular health, emphasizing its importance in regulating tissue blood flow, vascular remodeling, and protecting the endothelium. In cardiovascular disease, dysregulation of NO signaling is implicated in various conditions, including hypertension, coronary heart disease, and heart failure. The review discusses pharmacological and non-pharmacological strategies aimed at increasing NO production or signaling, such as inhaled NO, organic nitrates, phosphodiesterase type 5 (PDE5) inhibitors, and sGC activators. Finally, the review highlights the potential of NO-Ferroheme as a signaling entity in the cardiovascular system, suggesting new avenues for therapeutic intervention. Despite the extensive research, questions remain about the chemical nature of NOS-derived bioactivity and the precise mechanisms of NO signaling in complex physiological processes.