Fluoropyrimidine regimens in gastrointestinal oncology have evolved empirically. Bolus 5-fluorouracil (5-FU)-containing combinations now coexist with continuous metronomic schedules and oral prodrugs, while immune checkpoint inhibitors (ICIs) seek chemotherapy partners for microsatellite-stable (MSS) gastrointestinal cancers. This review examines the intersection of bolus omission, metronomic scheduling, and biomarker-selected immunochemotherapy and proposes a shift from dose-based to exposure-based paradigms.