In 1516, a group of cardinals conspire to assassinate the pope in the Vatican. Pope Leo X (a Medici, remember) was disliked for living an excessively lavish lifestyle, throwing money left and right towards whatever ends he desired. The Catholic church's own leaders are dissatisfied with the institution and, most of all, with their pope. Before the conspirators can execute their plan, however, the pope learns of their treachery, and in a very short time frame each conspirator dies of "food poisoning." The pope, it would seem, cannot be stopped.
The following year, 1517, Martin Luther publishes his 95 Theses—another attempt to dethrone the pope, this one much more successful—wherein he attacks the idea of papal indulgences (or the economic sale of salvation from sins). The new printing press helps Luther to spread his ideas like wildfire, and the church splits in two. The schism is called the Protestant Reformation.
Although the Catholic church would greatly feel the effects of the Protestant Reformation, the Medici themselves will only acquire more power. Giulio de Medici becomes the next pope, Pope Clement VII and Catherine de Medici, after marrying the French king, becomes Queen of France.