Tributyrin is a prodrug of natural butyrate. It is a neutral short-chain fatty acid triglyceride that is likely to overcome the pharmacokinetic drawbacks of natural butyrate as a drug. Tributyrin has potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells. Compared with butyrate, tributyrin has more favorable pharmacokinetics and is well tolerated. Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. Tributyrin may, at least in part, exert its growth-reducing and differentiation-inducing effect in Caco-2 cells by an upregulation of the vitamin D receptor; this may provide a useful therapeutic approach in chemoprevention and treatment of colorectal cancer. In phase I study of the orally administered tributyrin there was no consistent increase in hemoglobin F. Peak plasma butyrate concentrations occurred between 0.25 and 3 h after dose. Development of tributyrin as an anticancer agent was discontinued.