Apolipoprotein E (apoE) is a critical molecule in lipid metabolism, which also plays important roles in the occurrence and development of several kinds of cancers by regulating processes including cell proliferation, energy metabolism, oxidative stress and innate immune, etc., and shows influence in patients’ response to treatment. Therefore, apoE has become a potential biomarker and treatment target for cancer. Further research of apoE will help us build deep and systematic understanding of etiology of cancer to promote the prevention and to develop new therapeutic strategies for cancer. In this review, we introduced the properties of apoE from the views of biophysics, biochemistry, molecular biology, evolution and epidemiology, in which we demonstrated the similarities and differences among the structures of 3 subtypes of apoE; we also recapitulated the role of apoE in the genesis and development of cancers in main types of malignancies including gastric cancer, colorectal cancer, hepatobiliary cancer, melanoma, pancreatic cancer, etc.; we summarized the relationship between apoE and the hallmarks of cancer, highlighting the position of apoE in immune system and its critical role for understanding the different nature of immunological background of cancers originated from different organs, and discussed its potential value for application as tumor biomarkers and therapeutic targets by demonstrating the structures of its subtypes. We further discussed the possibility of transferring the drug designing strategy of “structure corrector” from neurology to oncology.