This article reviews recent advances in nitric oxide (NO) signaling and regulation in the cardiovascular system. NO, produced by endothelial NO synthase (eNOS), is crucial for vascular homeostasis. Reduced NO production or increased scavenging during disease conditions contribute to endothelial dysfunction. NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches to increase NO bioactivity have been studied extensively. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins and directly activate the sGC-cGMP-PKG pathway. Red blood cell interactions with the endothelium in vascular NO homeostasis have gained attention, especially in cardiometabolic disease. The article discusses both classical and non-classical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. It also highlights the role of red blood cells, the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system. Existing and potential pharmacological treatments, as well as dietary components influencing NO generation and signaling, are covered. The review also discusses toxicological issues related to N-nitrosoamines from diet and drugs. The article emphasizes the importance of NO in cardiovascular health and disease, including its role in vascular homeostasis, protection against disease, and its involvement in various physiological processes. It also discusses the impact of NO dysregulation in cardiovascular disorders, such as hypertension, coronary heart disease, peripheral artery disease, heart failure, and stroke. The review highlights the potential of pharmacological and non-pharmacological strategies to increase NO production and signaling, including inhaled NO, organic nitrates, PDE5 inhibitors, sGC activators, and hybrid NO donors. The article also discusses the role of statins, hydralazine, and drugs targeting the renin-angiotensin-aldosterone system (RAAS) in enhancing NO signaling. Overall, the review underscores the significance of NO in cardiovascular health and disease and the potential for therapeutic interventions targeting NO signaling.This article reviews recent advances in nitric oxide (NO) signaling and regulation in the cardiovascular system. NO, produced by endothelial NO synthase (eNOS), is crucial for vascular homeostasis. Reduced NO production or increased scavenging during disease conditions contribute to endothelial dysfunction. NO can also be generated via the nitrate-nitrite-NO pathway. Dietary and pharmacological approaches to increase NO bioactivity have been studied extensively. Recent studies show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins and directly activate the sGC-cGMP-PKG pathway. Red blood cell interactions with the endothelium in vascular NO homeostasis have gained attention, especially in cardiometabolic disease. The article discusses both classical and non-classical pathways for NO generation in the cardiovascular system and how these can be modulated for therapeutic purposes. It also highlights the role of red blood cells, the nitrate-nitrite-NO pathway, and therapeutic opportunities related to the NO system. Existing and potential pharmacological treatments, as well as dietary components influencing NO generation and signaling, are covered. The review also discusses toxicological issues related to N-nitrosoamines from diet and drugs. The article emphasizes the importance of NO in cardiovascular health and disease, including its role in vascular homeostasis, protection against disease, and its involvement in various physiological processes. It also discusses the impact of NO dysregulation in cardiovascular disorders, such as hypertension, coronary heart disease, peripheral artery disease, heart failure, and stroke. The review highlights the potential of pharmacological and non-pharmacological strategies to increase NO production and signaling, including inhaled NO, organic nitrates, PDE5 inhibitors, sGC activators, and hybrid NO donors. The article also discusses the role of statins, hydralazine, and drugs targeting the renin-angiotensin-aldosterone system (RAAS) in enhancing NO signaling. Overall, the review underscores the significance of NO in cardiovascular health and disease and the potential for therapeutic interventions targeting NO signaling.