In those cells that use glycolysis to generate their ATP under normoxic conditions (e.g. white skeletal muscle) lactic acid must leave the cell if the intracellular pH is not to drop. This applies to all cells under hypoxic / anoxic conditions. Other cells take up lactic acid for oxidation (e.g. heart, neurons and red skeletal muscle) or gluconeogenesis (liver and kidney). In all cases lactic acid must be transported across the plasma membrane and this process is mediated by members of the monocarboxylate transporter (MCT) family of which 14 members are known to be encoded by the mouse and human genomes. Of these, only four (MCT1, MCT2, MCT3 and MCT4) have been demonstrated to catalyses proton-linked transport of lactate. Transport is not energy linked and the direction of net movement of lactate depends on the prevailing lactate and proton gradients. MCT1 is ubiquitously expressed and has K_m values for L-lactate and pyruvate of about 1 and 4 mM respectively. MCT4 is the major isoform expressed in those cells such as white muscle fibres that rely on glycolysis under normoxic conditions and has K_m values for L-lactate and pyruvate of about 25 and 150 mM respectively. The tissue expression of MCT2 (K_m values 1 and 0.1 mM respectively) is highly species dependent but tends to be found in tissues that require a high affinity uptake system for lactic acid such as liver, kidney and neurons. MCT3 expression is confined to the retinal pigment epithelium and choroids plexus but its kinetic characteristics have not been well-defined (Halestrap & Meredith, 2004; Meredith & Christian, 2008). MCTs require a single transmembrane (TM) ancillary glycoprotein, either basigin or embigin, to be properly expressed at the plasma membrane. MCT1, MCT3 and MCT4 prefer basigin whilst MCT2 prefers embigin. These ancillary proteins have an extracellular domain containing two or three immunoglobulin folds and a short intracellular domain. It is the latter together with the TM domain that are important for their interaction with the MCT and site-directed mutagenesis has shown that the TM domain of basigin interacts with both TM 3 and TM 6 of MCT1. Further site-diretced mutagensis has enabled the identification of amino acids that are essential for the translocation cycle of MCT1 and other residues that are involved with substrate and inhibitor binding. This information has been used to generate a molecular model of MCT1 in both inward and outward conformations and a likely translocation cycle mechanism that are based on the published structure of the E. Coli glycerol-3-phosphate transporter (Manoharan et al., 2006 and unpublished data). The expression of MCTs is subject to both transcriptional and post-transcriptional regulation but of particular interest is the up-regulation of MCT4 by hypoxia through a Hypoxia Inducible Factor 1α (HIF-1α) mediated increase in gene transcription (Ullah et al., 2006). Recently, a novel class of MCT1 specific inhibitors (K_i values ~ 1nM) have been described that are useful pharmacological tools to study the importance of lactate transport via MCT1 in different physiological and pathological scenarios (Murray et al., 2005).