First mentioned in 1135, the remains found along the ancient road date back to Gallo-Roman times. Once an Austrian seigneury, Issenheim was burnt down during the Thirty Years' War. The town is famous for its altarpiece painted by Mathias Grünewald. This famous painting depicts the plants used to treat "St. Anthony's fire". Today, part of the convent has been converted into a museum dedicated to the history of the Antonine Order. Also marked by the industrial and textile era, Issenheim's history is reflected in the architecture of the Gast spinning mill.

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