In games with the Spanish, Portuguese and all non-catholic factions I tend to build a lot of assassins to get rid of those annoying priests that convert the people away from the true faith.

I start them out on a training run against a small rebel mob that I leave standing about in the territory where the assassins are trained (for Spain that is Toledo, for Portugal that's Lisbon) and try to kill the rebel captain until they "level up". Then I send them after Moorish captains foolish enough to be spotted walking about alone in their territory. Usually by the time they've butchered some captains they are skilled enough to take out minor generals.

Two things I have noticed from observation. Building assassins in a city with an assassin guild and some form of "smith" usually gives them a weapon that gives them a +1 to assassination.

Sabotaging stuff tends to give the assassin retinue that only improves their sabotage skill, before any general subterfuge upgrades. Having a general member around with a bonus to agent recruitment is also very very useful as this reduces the cost of the assassin by quite a lot eventually.

At least half of all the assassins I trained also get retinue that drastically improve their subterfuge for assassination, or for all things.

In one game I killed 8 consecutive popes (all from Poland and Hungary) and then my cardinal got elected and the elite assassin that killed all those popes (added up, he must have had an subterfuge for assassination of 20-something)

One thing I did notice. When you use assassins a lot, generals from neighboring factions, even those you do not harass with your assassins gain all kinds of retinue increasing their security although that may have been because another faction was attempting to assassinate their leaders a lot.