Colorectal cancer (CRC) is a common cancer with poor prognosis and high mortality. There is growing information about the factors involved in the pathogenesis of CRC. However, the knowledge of the predisposing factors is limited. The development of CRC is strongly associated with the Wingless/Integrated (Wnt) signaling pathway. This pathway comprises several major target proteins, including LRP5/6, GSK3β, adenomatous polyposis coli (APC), axis inhibition protein (Axin), and β-catenin. Genetic variations in these components of the Wnt signaling pathway may lead to the activation of β-catenin, potentially increasing the proliferation of colorectal cells. Because of the potentially important role of the Wnt signaling pathway in CRC, we aimed to review the involvement of different mutations in the main downstream proteins of this pathway, including LRP5/6, APC, GSK3β, Axin, and β-catenin. Determination of the genetic risk factors involved in the progression of CRC may lead to novel approaches for the early diagnosis of CRC and the identification of potential therapeutic targets in the treatment of CRC.