Nitric oxide (NO) is a central regulator of cardiovascular function, influencing vascular tone, platelet activity, and inflammatory signaling. Despite decades of work defining its molecular pathways, translation into consistent clinical application has remained uneven, with findings across experimental, biomarker, and therapeutic studies often appearing inconsistent. Part of this variability reflects how NO behaves under different biological conditions. Its effects are shaped by where it is produced, how much is generated, and the biochemical environment in which it operates. Under some conditions, NO supports vascular homeostasis, while in others it contributes to oxidative and nitrosative stress, a pattern we refer to as the nitric oxide paradox. This review revisits commonly used NO-related biomarkers, including nitrate/nitrite (NOx), asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine, and considers why their clinical interpretation remains inconsistent. It also examines the limitations of NO-based therapies, where short half-life, systemic exposure, and limited control over delivery continue to constrain outcomes. Rather than viewing these findings as conflicting, this article considers them as reflections of how NO signaling shifts across different physiological contexts. We organize NO signaling according to four interacting determinants: enzymatic source, magnitude and duration of production, cellular compartment, and the surrounding redox environment. Framing NO biology in this way may help explain variability in both diagnostic and therapeutic settings and clarify where current approaches remain limited.