The association between fever and neutropenia and the risk for life-threatening infections in patients receiving cytotoxic chemotherapy has been known for 50 years. Indeed, infectious complications have been a leading cause of morbidity and mortality in patients with cancer. This review chronicles the progress in defining and developing approaches to the management of fever and neutropenia through observational and controlled clinical trials done by single institutions, as well as by national and international collaborative groups. The resultant data have led to recommendations and guidelines from professional societies and frame the current principles of management. Recommendations include those guiding new treatment options (from monotherapy to oral antibiotic therapy) and use of prophylactic antimicrobial regimens in high-risk patients. Of note, risk factors have changed with the advent of hematopoietic cytokines (especially granulocyte colony-stimulating factor) in shortening the duration of neutropenia, as well as with the discovery of more targeted cancer treatments that do not result in cytotoxicity, although these are still the exception. Most guiding principles that were developed decades ago-about when to begin empirical treatment after a neutropenic patient becomes febrile, whether and how to modify the initial treatment regimen (especially in patients with protracted neutropenia), and how long to continue antimicrobial therapy-are still used today. This review describes how the treatment principles related to the management of fever and neutropenia have responded to changes in the patients at risk, the microbes responsible, and the tools for their treatment, while still being sustained over the arc of time.