I like the *ahem* 'Death Starbase' idea

And space monsters
and the supernova - you could evacuate the planet with transports
How about the weakest civ invents a Dyson Sphere and encases a star in a massive, habitable shell.
I also like the dodgy ship builders, especially for federalist governments who are most likely to cut corners where finance is involved.
An outbreak of flower power, you government and population suddenly become pacifists
Nebulas that provide a bonus and penalty to any ships inside them, but at some point in the game form a new star system.
An extinction event, a huge asteroid dumps on the planet wiping out the major life forms, perhaps resulting in either a change of planet quality & type or the emergance of a minor race.
Mad scientist develops new DNA strain and accidentally converts a whole planet to a minor race who are similar to it's parent race, but really, really superior, arrogant and irritating.
The Galactic Star Beast (fictional religious diety) Cult takes over the civilisation and declares a crusade on every other race in the Galaxy. Death or Glory, only total annihilation of themselves or everyone else will suffice.
Double agents. Every agent you have that's not in use is now working for an unknown (perhaps minor race) faction and they get used against you. Only building more agents or counter espionage will stop them.
Defection!!! That massive battle fleet gathering on your (heheh, or their) border actually wants to defect as the mess food is better and the uniforms not as itchy.
Permanant wormholes appear.
Technology virus - a technology virus spreads through the universe. Any race in contact with the virus cannot research any more techs and loses a few into the bargain. Any ship, planet, SB etc that comes within a few parsecs of an infected planet, ship etc... has a chance of contracting the virus. "Give me 100000bc and I promise not to send my infected ships into your home system"
Slavery - Tourists are disappearing. Lose some income from tourism, lose some influence but gain population boosts and manufacturing bonuses.
The Space Lurgi - yeuch, I don't know what's happened to them, but that disease has made them really ugly, smelly and generally unpleasant. Huge drop in influence (as being cornered by a hugely influencial race can be really hard to defend against, time to develop a Space Lurgi, that will show the smug, good looking, suave bastards).