Transmembrane protein tetraspanins either promote or suppress tumor invasion and metastasis. Their effects on tumor progression depend on the multimolecular transmembrane complex called tetraspanin-enriched microdomain (TEM) and are attributed to the alterations in the (1) motogenic and mitogenic behaviors and/or (2) microenvironmental interactions of tumor cells. As the modifiers of cell membrane structure and function, tetraspanins have emerged as diagnostic and prognostic markers and therapeutic targets for tumor progression.