Fever is defined as a core body temperature >38.0C (100.4F), representing an upward shift in the hypothalamic set point mediated by prostaglandin E2 (PGE2). During infection, macrophages release endogenous pyrogens (IL-1, IL-6, TNF-alpha) that stimulate cyclooxygenase-2 (COX-2) in the hypothalamic organum vasculosum, producing PGE2. PGE2 raises the thermoregulatory set point, triggering heat conservation (vasoconstriction, shivering) until body temperature matches the new set point. Fever is a beneficial host defense mechanism that enhances immune function: neutrophil migration, lymphocyte proliferation, and antimicrobial protein production are all augmented at febrile temperatures. The risk of serious bacterial infection (SBI) is stratified by age: neonates <28 days have the highest risk (10-15%) due to immature immune systems, warranting aggressive evaluation. Infants 29-60 days have intermediate risk (5-10%), while children >60 days with no high-risk features have low risk (<1%). The Rochester, Philadelphia, and Boston criteria help stratify risk in febrile infants.