Granulocyte colony-stimulating factor (G-CSF) has been used in the clinic for 
more than 2 decades to treat congenital and acquired neutropenias and to reduce 
febrile neutropenia before or during courses of intensive cytoreductive therapy. 
In addition, healthy stem cell donors receive short-term treatment with G-CSF 
for mobilization of hematopoietic stem cells. G-CSF has also been applied in 
priming strategies designed to enhance the sensitivity of leukemia stem cells to 
cytotoxic agents, in protocols aimed to induce their differentiation and 
accompanying growth arrest and cell death, and in severe aplastic anemia and 
myelodysplastic syndrome (MDS) to alleviate anemia. The potential adverse 
effects of G-CSF administration, particularly the risk of malignant 
transformation, have fueled ongoing debates, some of which can only be settled 
in follow-up studies extending over several decades. This specifically applies 
to children with severe congenital neutropenia who receive lifelong treatment 
with G-CSF and in which the high susceptibility to develop MDS and acute myeloid 
leukemia (AML) has now become a major clinical concern. Here, we will highlight 
some of the controversies and challenges regarding the clinical application of 
G-CSF and discuss a possible role of G-CSF in malignant transformation, 
particularly in patients with neutropenia harboring mutations in the gene 
encoding the G-CSF receptor.