The story loosely follows the life of Wyatt Gwyon, a Calvinist minister's son from rural New England. He initially plans to follow his father into the ministry. However, he is inspired to become a painter by The Seven Deadly Sins , Bosch's painting in his father's possession. He leaves and travels to Europe to study painting.
Discouraged by a corrupt critic and frustrated with his career he moves to New York. He meets Recktall Brown, a capitalistic collector and dealer of art, who makes a Faustian deal with him. Wyatt creates paintings in the style of Flemish and Dutch masters (such as Hieronymous Bosch, Hugo van der Goes, and Hans Memling), forges their signature, and Brown will sell them as newly discovered antique originals.
Soon Wyatt is discouraged, and goes home only to find his father converted to Mithraism and losing his mind. Back in New York, he tries to expose his forgeries, then travels to Spain where he visits the monastery where his mother was buried, restores old paintings, and tries to find himself in his search for authenticity. At the end, he moves on to live his life "deliberately".
Interwoven are the stories of many other characters, among them Otto, a struggling writer, Esme, a muse, and Stanley, a musician. The epilogue follows their stories further. In the final scene Stanley achieves his goal by playing his work at the organ of the church of Fenestrula "pulling all the stops". The church collapses, killing him, yet "most of his work was recovered ..., and is still spoken of, when it is noted, with high regard, though seldom played."
The major part of the novel takes part in the late 1940s and early 1950s.