There is no radical cure for all cancer types. The most frequently used therapies are surgical treatment, radiotherapy and chemotherapy. However, recrudescence, radiation resistance and chemotherapy resistance are the most challenging issues in clinical practice. To address these issues, they should be further studied at the molecular level, and the signaling pathways involved represent a promising avenue for this research. In the present review, we mainly discuss the components and mechanisms of activation of the Notch and Wnt signaling pathways, and we summarize the recent research efforts on these two pathways in different cancers. We also evaluate the ideal drugs that could target these two signaling pathways for cancer therapy, summarize alterations in the Notch and Wnt signaling pathways in cancer, and discuss potential signaling inhibitors as effective drugs for cancer therapy.