Chronic constipation remains a therapeutic challenge for today's physicians. Traditional approaches include use of fiber, osmotic laxatives, stimulant laxatives, prokinetic agents, biofeedback training, and surgery. These often are tried sequentially and episodically and have little evidence of long-term efficacy. Patients often report inadequate relief of symptoms. There is room for improvement, therefore, in the therapy of chronic constipation. Future advances largely will be based on insights into the enteric nervous system (ENS), the structure and function of which is being revealed in great detail. Manipulating the ENS pharmacologically offers the opportunity to reprogram this key control system to improve bowel function. For example, interneurons in the ENS display 5-HT4 receptors, activation of which enhances the peristaltic reflex. Prokinetic agents that stimulate those receptors, such as tegaserod and prucalopride, have demonstrated efficacy as investigational agents for the treatment of chronic constipation in large studies. Less well studied investigational drugs with presumed activity in the ENS include opiate antagonists and the nerve growth factor neurotrophin-3. Both of these types of agents have been shown to be effective in small groups of patients with constipation. Another approach under development is to stimulate colonic fluid secretion by opening chloride channels in the epithelium pharmacologically. Existing non-pharmacological treatments that can be improved include biofeedback training for pelvic floor dysfunction and surgery. Future developments include investigation of electrical stimulation of the colon and use of stem cells to repopulate degenerated populations of neurons, interstitial cells of Cajal, or smooth muscle cells.