De Morgan began lessons at the age of 15, followed by prize-winning studies at South Kensington and Slade Schools. Her exhibition debut was in 1876 at the Dudley Gallery and followed that with a show at the Grosvenor Gallery, where she would exhibit regularly. In 1887 she married William De Morgan, ceramicist and associate of William Morris, with whom she shared a deep interest in spiritualism. Her preferred subjects included sacred and allegorical figures and scenes, and legends with a moral or social message. Together, they devised a painting method utilizing glycerine which, though too troublesome to pursue, produced the clear, bright tones she sought. In 1916, her horror of the war led her to mount an exhibition of 13 works for the benefit of the Red Cross.
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