Dysregulation of galectin expression is frequently observed in cancer tissues. Such an abnormal expression pattern often correlates with aggressiveness and relapse in many types of cancer. Because galectins have the ability to modulate functions that are important for cell survival, migration and metastasis, they also represent attractive targets for cancer therapy. This has been well-exploited for extracellular galectins, which bind glycoconjugates expressed on the surface of cancer cells. Although the existence of intracellular functions of galectins has been known for many years, an increasing number of studies indicate that these proteins can also alter tumor progression through their interaction with intracellular ligands. In fact, in some instances, the interactions of galectins with their intracellular ligands seem to occur independently of their carbohydrate recognition domain. Such findings call for a change in the basic assumptions, or paradigms, concerning the activity of galectins in cancer and may force us to revisit our strategies to develop galectin antagonists for the treatment of cancer.