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This article traces the history of 5 cardiac drugs—Aspirin, Atropine, Digitalis, Nitroglycerine, and Quinidine—that have been in continuous use for centuries and some for longer. Four of the 5 started life as botanicals and 4 have as also served widely varied functions far removed from their current purposes. Collectively, they have played a role in the history of royalty, religious leaders, assassinations and military campaigns in addition to their place in medical therapy. Their present clinical status has evolved from long-term clinical observation without the need for controlled clinical trials, detailed statistical analyses or FDA approvals. This review of their background illustrates the varied means by which markedly different substances from widely separated sources can come together to participate in the management of circulatory disorders.