Introduction. Penile fibrosis has been conceptually identified with the plaque that develops in the tunica :albuginea in Peyronie's disease (PD), or with localized processes induced in the corpora cavernosa by ischemic or traumatic events. Recently, it has been proposed that a diffuse, progressive, and guilder intracorporal fibrosis, which affects also the media of the penile arteries, is responsible for vasculogenic erectile dysfunction (ED) associated with aging, smoking, diabetes, hypertension, and post-radical prostatectomy. These processes differ in etiology, tinge course, target cells, and treatment, but have many features in common. Aim. To review the literature pertaining to fibrosis in the penis, related to PD and ED. Methods. PubMed search for pertinent publications mainly during 2001-2008. Results. This review focuses initially on PD and then deals with studies on ED in animal cell culture models, discussing sonic of the pathophysiological similarities between tunical fibrosis ill PD mid corporal fibrosis ill corporal veno-occlusive dysfunction (CVOD), and emerging therapeutic strategies. The role of profibrotic factors, the excessive deposit of collagen fibers and other extracellular matrix, the appearance of a synthetic cell phenotype ill smooth muscle cells or the onset of a fibroblast-myofibroblast transition, and in the case of the corporal or penile arterial tissue the reduction of the smooth muscle cellular compartment, are discussed. This histopathology leads either to localized plaques or nodules ill penile tissues, or to the diffuse fibrosis causing impairment of tissue compliance that underlies CVOD and arteriogenic ED. The antifibrotic role of the sustained stimulation of the nitric oxde/cyclic guanosine monophosphate pathway in the penis and its possible relevance to exogenous allot endogenous stein cell differentiation is also briefly presented. Conclusions. Fibrotic processes in penile tissues share a similar cellular and molecular pathophysiology and common endogenous mechanisms of defense that have inspired novel pharmacological experimental approches. Gonzalez-Cadavid NF: Mechanisms of penile fibrosis. J Sex Med 2009;6(suppl 3):353-362.