The Thirty Years War (1618–1648)

Ernest Crofts' A Scene from the Thirty Years' War

After the introduction of Calvinism to the Palatinate in 1559, the region became one of the major centres for the religion in Europe.  This adoption of Calvinism made the area one of the key fault lines in the religious wars that would dominate Europe over the next 200 year. The most notable of these wars became known as the Thirty Years War.
As anyone who has witnessed modern history will know, wars rarely have a single cause.  The Thirty Years War was primarily between the Protestant states of Europe and the Catholic ones led by the Holy Roman Empire.  The Palatinate was caught up in the the Thirty Years War in what is referred to as the Palatinate Campaign.  This lasted from approximately 1620 - 1622.  The main participants of the campaign were the Spanish who attacked from the Spanish Netherlands (modern day Belgium, Luxembourg) and the English who were garrisoned in the Palatinate.  This campaign ended with a Spanish victory and they occupied the Palatinate.
The war itself would drag on until 1648 where it would finally end with the Peace of Westphalia.  The result of this peace was that the Palatinate was effectively split into Catholic Upper Palatine to the north of Bavaria and a Protestant Lower Palatine along the Rhine. The Lower Palatine corresponds approximately to the modern state of Rhineland Palatinate.
The Thirty Years War was a disaster for the Palatinate.  By the end of it the state was devastated.  The new Emperor Palatinate, Charles Louis embarked on a program to rebuild the battered state. Charles Louis also adopted a pro-French policy that included marrying his daughter, Elizabeth Charlotte, to Philippe of France the brother of Louis XIV.  This decision would have momentous consequences for the palatines.