Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signaling and many types of human cancers was established more than a decade ago, no Wnt signaling inhibitors have made it into the clinic so far. One reason for this is that no pathway-specific kinase is known. Additionally targeting the protein-protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance. Wnt/β-catenin signaling is involved in virtually all aspects of embryonic development and in the control of the homeostasis of adult tissues. Encouragingly however, in recent years first successes with Wnt-pathway inhibitors have been reported in mouse models of disease. In this review we summarize possible roads to follow during the quest to pharmacologically modulate the Wnt signaling pathway in cancer.