In this article, we provide a hypothesis considering the potential effect of phosphodiesterase 5a inhibitors on cellulite. Cellulite is a significant cosmetic problem for many post-adolescent women. Its pathophysiology is complex and involves the presence of excess subcutaneous fat, the microcirculatory system, lymphatics and the extracellular matrix. Many diverse treatments have been tested to treat cellulite like iontophoresis, ultrasound, thermotherapy, pressotherapy, lymphatic drainage and electrolipophoresis which all enhance skin microcirculation. There have been several attempts to treat cellulite with drugs, but results were insufficient. Phosphodiesterases (PDE) are a superfamily of enzymes degrading adenosine monophosphate (cAMP) and cyclic guanosine monophoshpate (cGMP). Human fat cell lipolysis is mediated by both cAMP- and cGMP-dependent protein kinases. Indeed, high dose sildenafil pretreatment led to increased lipolysis in adipocyte cultures. That effect could not be attributed exclusively to either PDE3b or PDE5a inhibition, since sildenafil inhibited about 50% of the PDE3b activity in pretreated adipocytes. Sildenafil has a potential beneficial effect on skin microcirculation, as well as on tissue hypoxia. Transdermal or local route of administration should be considered.