Chemotherapy-induced febrile neutropenia (FN) is a medical emergency that may occur in patients with malignancies receiving myelosuppressive chemotherapy. FN requires early therapeutic intervention since it is associated with increased hospitalizations and high mortality risk of 5%-20%. FN-related hospitalizations are higher in patients with myeloid malignancies than in those with solid tumors due to the myelotoxicity of chemotherapy regimens and the compromised bone marrow function. FN increases the burden of cancer by causing chemotherapy dose reductions and delays. The administration of the first granulocyte colony-stimulating factor (G-CSF) filgrastim reduced the incidence and duration of FN in patients undergoing chemotherapy. Filgrastim later evolved into pegfilgrastim, which has a longer half-life than filgrastim and is associated with a lower rate of severe neutropenia, chemotherapy dose reduction, and treatment delay. Nine million patients have received pegfilgrastim since its approval in early 2002. The pegfilgrastim on-body injector (OBI) is an innovative device facilitating the time-released auto-injection of pegfilgrastim approximately 27 h after chemotherapy, as clinically recommended for the prevention of FN, thus eliminating the need for a next-day hospital visit. Since its introduction in 2015, one million patients with cancer have received pegfilgrastim using the OBI. Subsequently, the device was approved in the United States (US), European Union, Latin America, and Japan, with studies and a postmarketing commitment demonstrating device reliability. A recent prospective observational study conducted in the US demonstrated that the OBI substantially improved the adherence to and compliance with clinically recommended pegfilgrastim therapy; patients receiving pegfilgrastim the OBI experienced a lower incidence of FN than those receiving alternatives for FN prophylaxis. This review discusses the evolution of G-CSFs leading to the development of the OBI, current recommendations for G-CSF prophylaxis in the clinic, continued evidence supporting next-day pegfilgrastim administration, and improvements in patient care made possible with the OBI.