Myelosuppression secondary to chemotherapy remains a serious adverse effect of cancer therapy that causes high morbidity and mortality. Several current European and American guidelines recommend consideration of primary prophylaxis with colony-stimulating factors (CSFs) when the risk of febrile neutropenia is higher than 20 %. The main factors associated with a high risk of febrile neutropenia include the chemotherapy regimen, tumor type, and patient-related factors such as old age and/or comorbidities. The purpose of this paper is to summarize the most relevant clinical trials and updated recommendations of the main guidelines on the role of granulocyte colony-stimulating factors (G-CSFs) in febrile neutropenia, examining whether the combination of G-CSF with chemotherapy improves overall survival. Future directions for G-CSF use are also discussed.