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Certain substances are produced from almost all cells of the human body and act locally on the adjacent cells (paracrine) or on their own secreting cells (autocrine)—these ubiquitous compounds are referred to as autacoids. Histamine and serotonin, the most versatile autacoids, are involved in the regulation of many of the nervous system, cardiovascular system, and gastrointestinal system functions. The structure, chemistry, biosynthesis, metabolism, receptors, and pathophysiological effects of histamine and serotonin are elaborated. The pharmacological properties—including the mechanism of action, pharmacological effects, therapeutic uses, and adverse effects of antihistamines, triptans, among others are detailed. The chapter includes discussion on the vasoactive peptides—bradykinin and kallidin and on ergot alkaloids. The pharmacotherapy of migraine is also explained.