Understanding tumor metabolism is important for the development of anticancer therapies. Immunohistochemical evaluation of colorectal adenocarcinomas showed that cancer cells share common enzyme/transporter activities suggestive of an anaerobic metabolism [high lactate dehydrogenase 5 (LDH5)/hypoxia-inducible factor αs (HIFαs)] with high ability for glucose absorption and lactate extrusion [high glucose transporter 1 (GLUT1)/monocarboxylate transporter (MCT1)]. The tumor-associated fibroblasts expressed proteins involved in lactate absorption (high MCT1/MCT2), lactate oxidation (high LDH1 and low HIFαs/LDH5), and reduced glucose absorption (low GLUT1). The expression profile of the tumor-associated endothelium indicated aerobic metabolism (high LDH1 and low HIFαs/LDH5), high glucose absorption (high GLUT1), and resistance to lactate intake (lack of MCT1). It is suggested that the newly formed stroma and vasculature express complementary metabolic pathways, buffering and recycling products of anaerobic metabolism to sustain cancer cell survival. Tumors survive and grow because they are capable of organizing the regional fibroblasts and endothelial cells into a harmoniously collaborating metabolic domain. (Cancer Res 2006; 66(2): 632-7)