Myelosuppression and neutropenia represent the major dose-limiting toxicity of cancer chemotherapy. Chemotherapy-induced neutropenia may be accompanied by fever, presumably due to life-threatening infection, which generally requires hospitalization for evaluation and treatment with empiric broad-spectrum antibiotics. The resulting febrile neutropenia is a major cause of the morbidity, mortality, and costs associated with the treatment of patients with cancer. Furthermore, the threat of febrile neutropenia often results in chemotherapy dose reductions and delays, which can compromise long-term clinical outcomes. Prophylactic colony-stimulating factor (CSF) has been shown to reduce the incidence, severity, and duration of neutropenia and its complications. Guidelines from the American Society of Clinical Oncology recommend the use of CSF on the basis of the myelosuppressive potential of the chemotherapy regimen. The challenge in ensuring the appropriate and cost-effective use of prophylactic CSF is to determine which patients would be most likely to benefit from it. A number of patient-, disease-, and treatment-related factors are associated with an increased risk of neutropenia and its complications. A number of clinical predictive models have been developed from retrospective datasets to identify patients at greater risk for neutropenia and its complications. Early studies have demonstrated the potential of such models to guide the targeted use of CSF to those patients who are most likely to benefit from the early use of these supportive agents. Additional prospective research is needed to develop more accurate and valid risk models and to evaluate the efficacy and cost-effectiveness of modeltargeted use of CSF in high-risk patients.