On June 22, 1527 Henry VIII confessed to Katherine of Aragon that his conscience was troubled over the legitimacy of their marriage. Katherine, along with her contemporaries and later historians, believed there were other reasons Henry wished to annul his 18 year marriage: the need to secure the succession with a male heir and his infatuation with Anne Boleyn. Historian Lacey Baldwin Smith in Henry VIII: The Mask of Royalty (1971) does not deny the reality of these latter factors in motivating Henry's actions, but he thinks that Henry's conscience was sincerely troubled by his marriage to Katherine.

Henry attributed his lack of sons to divine displeasure and referred to Leviticus, ch. 20, v. 21 ("And if a man shall take his brother's wife, it is an unclean thing: he hath uncovered his brother's nakedness; they shall be childless"). Since Henry's mistress Elizabeth Blount had given birth to a healthy son, Henry concluded that the fault lay with Katherine. A number of bad omens between 1524 and 1527 only confirmed his sense of God's wrath.

There were numerous precedents for the annulment, and Wolsey was sure that he could procure a papal annulment from Clement VII. Initially, Wolsey tried to handle the matter in his own legatine court, but Katherine refused to cooperate. She argued that since her marriage to Arthur had never been consummated there had never been a need for a papal dispensation, and there was no good reason to annul the marriage. Katherine's case was helped by the fact that her nephew, the Holy Roman Emperor Charles V, had conquered Rome and Pope Clement VII was at his mercy.

When French troops drove Charles V's army out of Rome in 1528, Clement authorized a hearing of the case in London under the authority of Wolsey and Lorenzo Campeggio, an authority on canon law. Pressure from Charles V, however, eventually forced the Pope to move the case to Rome. Henry was not pleased, and Wolsey fell from grace.

Anne Boleyn's pregnancy forced Henry to take immediate action. In April 1533 parliament denied the Pope's authority to judge spiritual cases in England, and in May 1533 the new Archbishop of Canterbury, Thomas Cranmer, ruled that Henry's marriage to Katherine was null and void. On June 1st, Anne Boleyn was crowned queen. Their child, Elizabeth, was born on 7 September 1533. In November 1534 parliament passed an Act of Supremacy making the king the "Supreme Head of the Church of England."