The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (Sodium Monocarboxylate Transporter), is dependent on external Na⁺ and is compatible with a 3:1 stoichioimetry between Na⁺ and monocarboxylates. A portion of the SMCT-mediated current is also Cl^--dependent, but Cl^- is not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrate K_m values near 100 µM, aside from acetate and D-lactate, for which the protein showed less affinity. SMCT showed strong inhibition by 1 mM probenecid or ibuprofen. In the absence of external substrate, a Na⁺-independent leak current is also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. Transport of monocarboxylates in anionic form is confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na⁺, short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na⁺/monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well-known for having antiproliferative and apoptosis-inducing activity in colon epithelial cells.