Priapism, in which penile erection persists in the absence of sexual excitation, is an enigmatic yet devastating erectile disorder. Current endeavors to manage the disorder suffer from a poor fundamental knowledge of the etiology and pathogenesis of priapism. These endeavors have remained essentially reactive, which commonly fail to avert its pathological consequences of erectile tissue damage and erectile disability, not to mention its psychological toll. The role of preventative management seems paramount with respect to priapism. As a prerequisite to formulating prevention strategies, gaining understanding of its pathogenic features and likely pathophysiologic mechanisms is viewed to be quite important. This review combined an analysis of clinicopathologic reports as well as a summary of clinical and basic science investigations on the subject to date. These assessments support the basic classification of priapism into low-flow (ischemic) and high-flow (nonischemic) hemodynamic categories, resulting from venous outflow occlusion and unregulated arterial overflow of the penis, respectively. In addition, consistent with the hypothesis that dysregulative physiology of penile erection accounts for some presentations of priapism, several plausible molecular mechanisms influencing the functional state of the erectile tissue are discussed. Current progress in the field suggests prevention possibilities using androgenic suppressive therapy, adrenergic agonist therapies, and effectors of the nitric oxide-dependent erection regulatory pathway in the penis. New ideas for prevention may emerge from targeting molecular mechanisms involved in regulating erectile tissue function.