<p>Infections contribute significantly to morbidity and mortality in patients with tumors. Particularly in patients with febrile neutropenia or neutropenic sepsis, timely diagnosis (e.g., immediately obtaining blood cultures) and antibiotic (AB) therapy are crucial to improve prognosis. However, the widespread use of ABs also has negative consequences, such as the spread of resistance, drug interactions, or side effects (e.g., organ toxicities). Additionally, recent studies show that impairment of the gut microbiota by ABs can induce further adverse effects, among them a&#xa0;reduced effectiveness of immunotherapeutics or increased complication rates under allogeneic hematopoietic cell transplantation. Therefore, rational use of AB in accordance with the principles of antibiotic stewardship (ABS) is of the greatest importance in patients with tumors. In this article, we provide an overview of AB therapy in cancer patients, with particular emphasis on the rational use of these agents. This includes the use of AB prophylaxis, the selection of initial AB therapy when infections occur, changes to treatment in the case of persistent fever, AB combination therapies, and the duration of treatment. Various studies have shown that both institutional standards and published recommendations regarding antimicrobial therapy are not followed in a&#xa0;significant proportion (&gt; 30%) of patients with tumors and infections. ABS programs and prospective monitoring of anti-infective management can improve adherence to guideline recommendations for the rational use of anti-infectives.</p>