This Practice Point commentary examines a recent systematic review by Bennett et al. that summarized 51 controlled trials of the erythropoiesis-stimulating agents (ESAs) darbepoetin and epoetin in patients with cancer. The review focused exclusively on the safety of this class of drugs. Key findings included an increased risk of venous thromboembolism (previously reported) and poorer overall survival (a new finding) in patients who received ESAs, compared with controls. This commentary discusses the evolving safety concerns regarding ESAs, and highlights the uncertainties about which groups of patients are at risk and whether some administration strategies are safer than others. The regulatory and reimbursement environments for these compounds are in flux, and until additional data are available, a conservative treatment approach is appropriate.