Headache is a very frequent symptom of infection. It has many possible underlying mechanisms, of which two or more can coexist in a single patient. It can be caused by direct stimulation of intracranial pain-producing structures, as in the case of brain abscesses, by irritation of the pachy- and leptomeninges, as in cases of bacterial or viral meningitis, or by a state of intracranial hypertension, as seen in obstructive hydrocephalus. There is no doubt that headache is often the first or the predominant symptom of serious, sometimes life-threatening, infectious diseases; certainly, it is a condition frequently encountered in all epidemiological studies. Indeed, it is estimated that over 60% of people have, at some point in their lives, experienced headache during an infection. This evidence leads to the need for a systematic approach to headache secondary to infection. This chapter provides some elements on pain mechanisms in systemic and intracranial infections and on the possible role of antimicrobial agents in the genesis of headache. The first section provides a detailed " etiology-based" description of the International Classification of Headache Disorders, 2nd edition (ICHD-II: Headache Classification Subcommittee of the International Headache Society, 2004), while the second section presents a " symptom-based" algorithm applicable in the first diagnostic assessment, according to the headache features and to the most frequently associated clinical manifestations during infections of the central nervous system (CNS).