As a matter of fact there were numerous revolts, large and small, throughout Ptolemaic history. Not all of them were necessarily out of a desire to see a non-Greek on the throne. Many were caused by the usual motivations behind ancient revolts. Soldiers who were paid too little or not at all, unfair levels of taxation and/or conscription, or general dissatisfaction with the ruling faction.

The most famous revolt occurred during the Secession of Upper Egypt circa 205 BC. During the reign of Ptolemy IV, Upper Egypt (the southern half of the country) attempted to break away from the Ptolemaic Kingdom under the native Egyptian Horwennefer.

Of course, the exact causes of the rebellion are unknown. Foreign wars had driven up taxes in Egypt, and might have contributed towards a general hostility towards the upper classes. The fact that the Egyptian priestly class, with their wealth and control over many aspects of local administration, largely supported the Ptolemaic dynasty is a sign that it may have been a class conflict.

Ptolemy IV had earlier conscripted 30,000 Egyptians, many of whom likely came from Upper Egypt, and trained them as hoplites. These forces helped to secure his victory over Antiochus III at the Battle of Raphia, but became problematic once they returned home. These discontent veterans played a large role in Horwennefer's revolt, as a standing army of battle-hardened soldiers.

The conflict between Upper Egypt and Ptolemaic controlled Lower Egypt consisted of both small scale skirmishes and larger, pitched battles. The Upper Egyptian forces attempted to cut off key Ptolemaic supply lines, while the Ptolemaic forces were devastated by wars in Syria fighting the Seleucid Empire. Nubia took advantage of the divisions in Egypt, and tried to press into Upper Egypt. This led to the loss of some southern territories to Nubia.

Both sides of the civil war found themselves simultaneously battling an external threat. Perhaps spurred on by the success of Horwennefer and Ankhwennefer, other small scale rebellions occurred throughout Egypt, including some within the Nile Delta, the Ptolemaic Dynasty's stronghold. This general anarchy characterized the conflict, which ended up continuing for roughly 20 long years.

Horwennefer died in battle around 5 years after coming to power, and Upper Egypt lost the major capital of Thebes. However, his successor Ankhwennefer was able to recover Thebes and ruled for an additional 15 years. Relatively late in time, Ankhwennefer managed to secure an alliance with Nubia, but he was still ultimately defeated by Ptolemy V. The great advantage that the Ptolemaic dynasty had was the wealth and agricultural output of the Nile Delta.

The secession lasted a generation, and had an even more lasting impact on Egypt. The Ptolemaic dynasty now understood that Upper Egypt was a force to be reckoned with, and that it could only be ruled with the consent of Egypt's elites. What followed was something of a renegotiation of power.

One of Ptolemy V's first actions was to make a series of proclamations about the rights and protections of Egyptians. Many concessions were made to the priestly class in Upper Egypt, for obvious reasons. Certain taxes were removed or decreased. Rebels were pardoned of all previous crimes, and the practice of press ganging Egyptians into naval service was also officially banned.

On the other hand, the Ptolemaic dynasty took steps to ensure that they had better control of Upper Egypt. Additional troops were stationed throughout Lower Egypt.

There would be further unrest and civil conflicts throughout the remaining 2nd and 1st Century BCE. In many ways the secession of Upper Egypt marked a turning point in the Ptolemaic dynasty's history. The aforementioned Syrian Wars were disastrous, and resulted in the Ptolemies losing most of their territories outside Egypt. Internal instability further weakened the already declining kingdom, and it never quite recovered.