Erythropoietin (Epo) has long been known to be the principal hematopoietic growth factor that regulates cellular proliferation and differentiation of the erythroid lineage. Recombinant Epo (rEpo) is frequently used in the prevention and treatment of anemia of chronic kidney disease (CKD) and in the treatment of anemia associated with cancer. The expression of the Epo receptor (EpoR) in certain cancer cells has raised the possibility that exogenous rEpo may have direct effects on tumor cells with potential for stimulation of proliferation and resistance to chemotherapy and possibly metastasis. With recent clinical trials reporting negative outcomes with rEpo in the treatment of cancer-related anemia, with increased mortality in those who received rEpo, it has become necessary for nephrologists to analyze and review the effect of use of rEpo in treatment of anemia of CKD in patients who may have current or previously treated malignancy. It is known that CKD patients have an increased prevalence of certain malignancies (Wong G et al. Association of CKD and cancer risk in older people. J Am Soc Nephrol. 2009;20(6):1341–1350). If a CKD patient develops cancer or has a previous history of cancer, there is a dilemma which faces the treating nephrologist with respect to the use of rEpo in this situation. So far this issue has been addressed infrequently in the nephrology literature, and the guidelines are unclear. This review describes Epo and EpoR biology, reviews use of rEpo for treatment of cancer-related anemia and makes a case to the nephrology community for the careful use of rEpo in CKD patients with cancer.