Prions are renowned for their role in neurodegenerative diseases in humans and animals. These are manifested as transmissible spongiform encephalopathies (TSEs) that result from the conversion of the normal glycosylphosphatidylinositol (GPI) anchored cellular prion protein (PrPc) to a misfolded, aggregated and pathogenic form, prion protein scrapie (PrPSc) via a post-translational process followed by the accumulation of PrP>Sc within the central nervous system. New research in this area has demonstrated that PrP is over-expressed in a variety of cancers including gastric, pancreatic and breast cancers, affecting the growth and invasiveness of these cancers as well as playing an important role in the acquisition of multi-drug resistant (MDR) gastric cancer. Prion-like doppel protein (Dpl), sharing 25% amino acid sequence homology to PrP and whose function remains elusive, has also been shown to exhibit a high level of expression in a number of cancers including acute myeloid leukemia's, myelodysplastic syndromes, gastric adenocarcinoma, anaplastic meningioma and astrocytomas. Furthermore, the tumour suppressor protein, p53, already known for its involvement in cancer development, has recently been shown to display prion-like tendencies. This review provides an overview of prions and prion-like proteins in mammals discussing their structure, function and role in cell function and disease. Furthermore, current research progress on the role of prion/prion-like proteins in the development, progression, and drug resistance of various cancers will be summarized. Potential implications for future development of new therapeutic treatments targeting prion and prion-like proteins will be discussed.