The Wnt signaling pathway has important functions in development, tissue homeostasis, and regeneration. Deregulation of canonical Wnt/β-catenin signaling is frequently found in various human cancers, particularly in colorectal cancer, and non-canonical Wnt signaling pathways also have been implicated in neoplasia. Colorectal cancer is a multipathway disease. Activation of Wnt signaling by both genetic and epigenetic alterations has been found to be important for both, initiation and progression of colorectal cancer. In addition, since Wnt signaling results in diverse downstream intracellular events, targeted inhibition of Wnt/β-catenin signaling at the most upstream site of this pathway is a rational and an advantageous new approach for the therapy of colorectal cancer.