Based on recent in vivo and in vitro findings, this review summarizes the molecular mechanisms that underline the action of PDE5 on intracellular metabolic pathways, the effects of the PDE5i, and the association between PDE5i and metabolic disorders, focusing on glucose metabolism disorders and on the potential therapeutic role of PDE5i to treat insulin resistance and type 2 diabetes. Here, PDE5A is linked to Insulin resistance.