I don't reload. What happens, happens.

I am on turn 120 as Venice on hard/very hard. My assassins have killed the King of France, the King of Spain and multiple family members from a variety of enemies. I have pushed several enemy cities into open rebellion due to destroying every law/order/religion building in a city and not allowing rebuilding. Properly trained assassins are great for destroying buildings and killing family members. That is what I use them for and I find them almost too powerful.

I will try to kill a cardinal every now and then but the odds are low. I keep very good relations with the Pope so I don't need to assassinate inquisitors. I don't try to kill enemy spies either. But spies aren't really much of a threat.

Again, I think assassins may be too powerful. In a "very hard/very hard" game, assassins may be necessary but in "hard/very hard" game, they give me too much of an advantage.