Inflammatory bowel disease (IBD) is fundamentally a relapsing and remitting disease appearing in forms of ulcerative colitis (UC) or Crohn's disease (CD) with a non-well-known etiology. With the hope to prevent adverse drug events and to increase the efficacy of therapies for IBD, in the recent years, other than new monoclonal antibodies such as infliximab, the novel phosphodiesterase inhibitors (PDEIs) have been introduced. Among PDE4Is, rolipram, OPC-6535, mesopram, roflumilast and tetomilast have shown beneficial effects in experimental colitis. Unfortunately until now, human studies have not been successful in showing significant superiority of PDE4Is in the treatment of IBD. Parallel with discovery of PDE4Is and their anti-inflammatory properties, inhibiting other PDE isoenzymes in immune and proinflammatory cells is on the way. PDE7Is have shown synergistic effect with PDE4Is and they may act similar to PDE3Is in experimental settings. Sildenafil as the PDE5I has shown good effects in experimental colitis by balancing oxidant-antioxidant status. Although the present data about PDE superfamily and their specific roles in gastrointestinal tract is limited but inhibitors of PDE4, PDE5 and PDE7 seem good candidates as the next generation of effective drugs. The synergistic anti-inflammatory effect of PDE4Is and PDE7Is is also important.