Postoperative ileus (POI) is a common clinical condition arising after almost every abdominal surgical procedure, leading to increased patient morbidity and prolonged hospitalisation. Recent advances in insight into the underlying pathophysiology have identified intestinal inflammation triggered by handling of the intestine as the main mechanism. Not only does the local inflammatory process compromise the contractile activity of the handled intestine, but it also activates inhibitory neural pathways and possibly triggers inflammation at distant untouched areas, leading to a generalised impairment of gastrointestinal motility. Macrophages residing in the muscularis externa and mast cells are the key players in this inflammatory cascade. Pharmacological interventions preventing the activation of these immune cells reduce the influx of leucocytes into the intestine, an effect associated with a reduction of the duration of POI. New potential therapeutic strategies to shorten POI based on these new insights will undoubtedly enter the clinical arena soon.