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Cayenne is the largest Francophone city in South America, which is a distinction most people do not expect to find on this continent and which says a great deal about how French Guiana operates. It is not a former colony or an overseas territory: French Guiana is a full department of France, with prefects instead of governors, electing representatives to the Assemblee Nationale in Paris, and paying for groceries with euros a short drive from the Amazonian jungle. The city was founded by the French in 1643, lost and recaptured from Dutch and English forces over the following decades, and has been French continuously since 1664.

The penal colony that operated on Devil's Island, in the archipelago offshore, ran from 1854 to 1938 and gave Cayenne an international notoriety it has spent decades recovering from.

The most famous prisoner was Alfred Dreyfus, the French Jewish officer falsely convicted of treason in 1894 and held there until his eventual exoneration; the Dreyfus affair became the defining political scandal of Belle Epoque France. The islands are now a nature reserve and the ruins of the prison structures remain, visited by boat from Kourou.