Recent studies have demonstrated that vasoconstriction in the erectile vasculature of the penis is mediated in part by RhoA/Rho-kinase signaling. However, this constrictor activity must be overcome to permit the vasodilation essential for erection. We hypothesize that the primary action of nitric oxide and other agents that cause penile erection is inhibition of the RhoA/Rho-kinase pathway, thereby allowing vasodilation and erection. This hypothesis, as well as experiments using hypogonadal and hypertensive animal models, are discussed in terms of the potential clinical value of Rho-kinase inhibitors for the treatment of erectile dysfunction.