NO/cGMP pathway in vascular smooth muscle cell (VSMC) is an important cellular signaling system for the regulation VSMC relaxation. We present a mathematical model to investigate the underlying mechanisms for this pathway. The model describes the flow of NO-driven signal transduction: NO activation of soluble guanylate cyclase (sGC), sGC and PDE-catalyzed cGMP production and degradation, cGMP-mediated regulation of protein targets including Ca²⁺-activated K⁺ channel and the myosin contractile system. Model simulations reproduce major NO/cGMP-induced VSMC relaxation effects including the intracellular Ca²⁺ concentration reduction and Ca²⁺ desensitization of myosin phosphorylation and force generation. Using the model, we examine several testable principles: (1) rapid sGC desensitization is caused by the end product cGMP feedback inhibition; a large fraction of the steady-state sGC population is in an inactivated intermediate state and cGMP production is limited well below maximum; (2) NO activates K_Ca with both cGMP-dependent and independent mechanisms; moderate NO concentration affects K_Ca via the cGMP-dependent pathway whereas higher NO is accommodated by cGMP-independent mechanism; (3) chronic NOS inhibition may cause underexpression of K⁺ channels including inward rectifier K_i and K_Ca; (4) Ca²⁺ desensitization of the contractile system is distinguished from Ca²⁺ sensitivity of myosin phosphorylation. The model integrates these interactions among the heterogenous components of the NO signaling system, and can serve as a general modeling framework for studying NO-mediated VSMC relaxation under various physiological and pathological conditions. New data can be readily incorporated into this framework for interpretation, and possible modification and improvement of the model.