CD147 is involved in many physiological functions, such as lymphocyte responsiveness, spermatogenesis, implantation, fertilization and neurological functions at early stages of development. Here we specifically review the role of CD147 in cancer. We focus on the following aspects: expression of CD147 in malignant versus normal tissues and its possible impact on prognosis, interaction of tumor cell-expressed CD147 with stroma cells and induction of matrix metalloproteinases, as well as the role of CD147 in tumor angiogenesis. The function of CD147 in supercomplexes with monocarboxylate transporters (MCT) and amino acid transporters such as CD98hc and large neutral amino acid transporter 1 (LAT1), as well as the functional contribution of CD147 in complexes with caveolin-1 and integrins, is discussed. Target validation experiments making use of CD147-directed RNAi and monoclonal antibodies are summarized. Finally, the relevance of CD147 as a target for therapeutic intervention in cancer patients is discussed.