Studies on the cellular prion protein (PrP) have been actively conducted because misfolded PrP is known to cause transmissible spongiform encephalopathies or prion disease. PrP is a glycophosphatidylinositol-anchored cell surface glycoprotein that has been reported to affect several cellular functions such as stress protection, cellular differentiation, mitochondrial homeostasis, circadian rhythm, myelin homeostasis, and immune modulation. Recently, it has also been reported that PrP mediates tumor progression by enhancing the proliferation, metastasis, and drug resistance of cancer cells. In addition, PrP regulates cancer stem cell properties by interacting with cancer stem cell marker proteins. In this review, we summarize how PrP promotes tumor progression in terms of proliferation, metastasis, drug resistance, and cancer stem cell properties. In addition, we discuss strategies to treat tumors by modulating the function and expression of PrP via the regulation of HSPA1L/HIF-1α expression and using an anti-prion antibody.