The prevention of chemotherapy-induced febrile neutropenia is important as it reduces hospitalization and is likely to improve quality of life. Several prophylactic strategies are available, although their use in patients with an anticipated short duration of neutropenia is controversial and not recommended. This paper presents the results of a review of the literature on the efficacy and cost-effectiveness of prophylactic antibiotics and/or granulocyte colony-stimulating factor, and also discusses the recommendations in current guidelines in view of recent publications. Both primary prophylactic granulocyte colony-stimulating factor and prophylactic antibiotics reduce the risk of febrile neutropenia considerably, and the addition of prophylactic granulocyte colony-stimulating factor to antibiotics is even more effective. As antibiotics, however, give rise to antimicrobial resistance and granulocyte colony-stimulating factor is expensive, tailoring of prophylaxis is clearly needed. This will increase the absolute clinical and economical benefits of prophylaxis. Patient-related, treatment-related and disease-related factors enhancing the risk of febrile neutropenia are discussed, including the, underrated, high risk of febrile neutropenia specifically in the first cycles of chemotherapy. Half of the patients developing febrile neutropenia during treatment do so in the first cycle of chemotherapy, which favors primary prophylaxis. The efficacy of secondary prophylaxis is not well documented. Finally, new interesting agents in the treatment and supportive care of solid tumors have become available, and these are discussed in relation to the incidence and prevention of febrile neutropenia.