Long-acting granulocyte colony-stimulating factor (G-CSF) preparations are increasingly used in the management of chemotherapy-associated neutropenia. Due to the fact that they only need to be administered once following chemotherapy, they are more convenient for patients and easier to use in the clinical routine for physicians than short-term G-CSF preparations. Although the efficacy of these growth factors is generally accepted, there remains some concern regarding their safety. In this article we address safety concerns for long-acting growth factors by providing basic information and available data around important clinical issues that may be helpful for the decision to use or not to use these factors in individual clinical situations. After a critical review of the literature, regarding theoretical considerations based on the physiology of hematopoiesis, data from clinical studies show that long-acting G-CSF preparations can be applied safely in approved indications and are broadly beneficial for patients at risk undergoing chemotherapy.