Following her father's divorce from her mother, Mary was stripped of her title of Princess of Wales, and deprived of her place in the line of succession. However, as Henry's wish for a brood of healthy children by a single wife never came true, and his only legitimate heir was a sickly son, he made a will before he died that placed Mary and Elizabeth in line to the throne after Edward. When Henry VIII died and Edward succeeded to the throne, Mary was thus again the direct heir. This concerned many Protestant nobles. Mary was a devoted Roman Catholic, and they were not only concerned about the restitution of the Roman Catholic Church in the country, but they were concerned about their land and wealth. Many nobles had profited greatly by the Reformation as land and goods that had once belonged to great monasteries and abbeys now belonged to them.

In a desperate attempt to prevent Mary succeeding to the throne, and as a way to preserve his own hold on power, John Dudley, Duke of Northumberland, Lord Protector of England as Edward was too young to rule, devised a plot to skip Mary and Elizabeth in the line of succession and pass the throne to Lady Jane Grey, great-granddaughter of Henry VII. In his will, Henry VIII had overlooked the Scottish line in favor of the descendants of his younger sister, Mary, and thus Frances Grey, Lady Jane's mother, became the next in line to the throne if Mary and Elizabeth were bypassed. Frances relinquished her claim to the throne in favor of her daughter, and John Dudley arranged a marriage between Jane and his son, Guildford. The Protector persuaded the young King to make a will eliminating Mary and Elizabeth from the succession because of illegitimacy, and consequently when Edward died in the July of 1553, Lady Jane Grey was proclaimed Queen in London.

Mary was not prepared to stand by and let John Dudley usurp the crown she believed was rightfully hers. The Tudor claimant had immense support in the country, and with her supporters, Mary made a valiant and successful bid for the throne, defeating the Duke's forces in days. After many years of struggle, Mary was finally proclaimed Queen of England, and it was a major political and personal triumph.

As soon as she was queen, Mary began the process of restoring the Roman Catholic faith in England. In 1555 this lead to a series of mass burnings of Protestants at the stake,  a policy that has earned Mary the title of Bloody Mary. Determined to do her duty and provide for the succession, Mary married her cousin, Prince Philip of Spain (later Philip II) in 1554, and the marriage was very unpopular amongst her Protestant subjects. In opposition to the impending marriage, Thomas Wyatt and his followers launched a rebellion, but it failed, and Wyatt and key supporters were imprisoned in the Tower. It was rumored that the purpose of the rebellion had been to crown Elizabeth, and believing this was true, Mary had her half-sister imprisoned in the Tower for suspected involvement. When no proof could be found against Elizabeth, she was released from the Tower and imprisoned in Woodstock Manor, Oxfordshire instead. 

Mary longed to have a child and for many months believed that she was actually pregnant, but the pregnancy turned out to be false. As Mary's health began to decline, perhaps due to cancer, the question of the succession became of prime importance. Still resenting what had happened to her mother, Mary was adamant that Elizabeth was not going to succeed her, but was persuaded to name Elizabeth her heir by her husband. Philip was concerned that if Elizabeth did not become Queen, the crown would fall into the hands of  half-French Mary, Queen of Scots. If Henry VIII's will was ignored, then by right of birth, Mary, Queen of Scots was the next heir after Elizabeth.  It was thus in Philip's interest to ensure that England stayed out of French hands. Mary finally named Elizabeth her heir, and her half-sister became Queen when Mary died on 17 November 1558.