Metastatic cancer cells increase glucose consumption and metabolism via glycolysis, producing large quantities of lactate. Recent work has shown that lactate efflux is mediated by monocarboxylate transporters (MCT), which are composed of a catalytic unit (MCT) and an accessory subunit (CD147), comprising the functional lactate transporter. CD147, an extracellular matrix metalloproteinase (MMP) inducer, is highly expressed in metastatic cancer cells. Because aerobic glycolysis is a hallmark of metastatic cancer, we examined whether increases in CD147 expression were linked to MCT expression in MDA-MB-231, a highly metastatic breast cancer cell line. MCT4 mRNA and protein expression were increased in MDA-MB-231 cells compared with cells derived from normal mammary tissue. MCT4 colocalized with CD147 in the plasma membrane and in membrane blebs shed from the cell surface. Small interfering RNA–mediated silencing of MCT4 impaired the maturation and trafficking of CD147 to the cell surface, resulting in accumulation of CD147 in the endoplasmic reticulum. Silencing MCT4 also resulted in fewer membrane blebs and decreased migration of MDA-MB-231 cells in vitro. Knockdown of CD147 resulted in loss of MCT4 in the plasma membrane and accumulation of the transporter in endolysosomes. These studies establish for the first time that increased expression of CD147 in metastatic cancer cells is coupled to the up-regulation of MCT4. The synergistic activities of the MCT/CD147 complex could facilitate migration of tumor cells by CD147-mediated MMP induction and lactate-stimulated angiogenesis and hyaluronan production. These data provide a molecular link between two hallmarks of metastatic cancer: the glycolytic switch and increased expression of CD147. [Cancer Res 2007;67(9):4182–9]