Equine practitioners often need to address problems associated with decreased gastro-intestinal motility in colic horses. Likewise, ileus is a notorious complication in horses that is predominantly seen after surgical intervention for small intestinal colic. Understanding the physiological mechanisms that are responsible for normal GI motility in horses and knowing which factors predispose horses to ileus, will help clinicians to better understand the clinical picture of a colic horse and to determine when and which prokinetic treatment should be chosen in any specific case. However, due to the lack of fundamental research, the knowledge of pharmacological activity pathways and therapeutic efficacy of prokinetic medication in colic horses is very fragmented. Often research results in other species are extrapolated to the horse, without any pharmacological evidence that enteral receptor populations that serve as pharmacological target to induce intestinal propulsion in these species are equally important in horses. A possible discrepancy in these receptor populations between humans and horses could partially explain the inconsistent clinical efficacy of human prokinetic agents such as cisapride, metoclopramide and domperidone in equine colic cases. Furthermore, due to the lack of large, double-blind multi-center clinical studies, the evaluation of the therapeutic efficacy of many prokinetic agents that are used in colic horses is very subjective. The lack of non-invasive techniques to evaluate gastro-intestinal motility in healthy and colic horses contributes to this subjectivity. As rule of thumb, it can be stated that for the treatment of stasis of the cranial part of the GI tract of horses, mainly lidocaine, metoclopramide and erythromycin should be used. In cases of colonic hypomotility, naloxone, neostigmine, erythromycin and lidocaine are the drugs of choice. With regard to sedation of colic patients, it should be mentioned that acepromazine and xylazine both will negatively influence GI motility to a lesser extent than the alpha 2 agonists detomidine and romifidine. However, in colic cases expressing shock and endotoxemia, the use of acepromazine is hampered by its pronounced hypotensive effects.