The point of no return?

[Epimetheus]

Epeirus went to crap when Pyrrhus died.

I wouldn't quite say that. Epeiros enjoyed a brief resurgance under Pyrrhos' son, Alexander, who managed to conquer Makedonia from Antigonos Gonatas around 260 BC. Had he managed to hold onto it, I think Epeiros could have achieved hegemony over Greece. Whether they'd have faired any better against the Romans than the Antigonids is another story.

[Titus Marcellus Scato]

I would say any empire or confederation is doomed when it starts fighting against itself (civil war) on a regular basis (not just a one-off). Repeated civil wars gravely weakened both the Seleucid and Ptolemaiac empires, so Rome could beat them later. Civil war destroyed the Roman Republic, Rome only survived by becoming an empire.

The Romans only beat the Gauls because they were constantly fighting each other, by the time they banded together against Rome, it was too late, too many warriors were already dead. Same goes for the Britons. Rome conquered through 'divide and rule' - persuading barbarian enemies to fight each other, fight on Rome's side against a rival tribe, or at least to stand aside and do nothing while Rome destroyed a rival tribe.

[fraoula]

Although it is impossible to point to only one event I believe that the Gaulish tribes could have survived Caesar's expedition had they not asked from the Germans to interfer a few decades prior. Still they had been fighting each other for centuries. Imagine what the belgae alone could had done had they been united against Caesar. He says that they alone could muster 200,000 troops.
As for the Seleucids I think that it was a matter of time before their empire crubmled. The persian administrative managment (also used by Alexander) had serious problems maintaining the satrapes loyalty who either rebeled and formed their own kingdoms or sided with foreign ones.

[gollum]

Its rally hard to tell, throughout history there are examples of Empires that survived on a thread.

[antisocialmunky]

It was pretty funny when that guy humiliated the envoys Ghengis Khan sent to set up trade agreements with the Persians.

I think that counts.

[Intranetusa]

Carthage's 2nd Punic War went to hell when Hasdrubal's reinforcement army was defeated in Spain.

As others have mentioned, the Gallic kingdoms were pretty much screwed by the time Rome came around since they had weakened themselves through centuries of civil war. Same for the Successor states.

Napoleon's empire went to hell when he decided to invade Russia. Germany's empire went to hell after they decided to invade Russia and declare war on the US.

Hideyoshi's invasion of the East Asian mainland was doomed before it even began because he was dumb enough to think he could conquer the Ming Empire.

Eastern Han Empire went to hell when the central authority gave too much power to military governors.

Roman Republic went to hell after the Sulla-Marian civil war, then Caesar-Pompey civil war, then Conspirator-Loyalist civil war, then Octavian-Anthony civil war.

It was pretty funny when that guy humiliated the envoys Ghengis Khan sent to set up trade agreements with the Persians.

I think that counts.

Humiliating a Mongol ambassadors was medieval equivalent to telling the US military to "drop a nuke on me."