PRESSURE
Your Villains should actively work towards their goals. If the Player Characters spend an extended amount of time resting or taking care of issues that are not related to an antagonist’s plans, then that antagonist will not sit idly and wait for the heroes to do something: they will get closer to their objective.
When a Villain’s plans advance, you must always clearly communicate it to the Players — perhaps with an appropriate Game Master scene, or through rumors and conversations the heroes have with NPCs in the game world. Don’t just surprise them with a casual “Oh yeah, did I mention this guy you didn’t know about has successfully rewritten reality?”
If you plan on having multiple Villains in your campaign at the same time — or if you play at very irregular intervals and it's hard to remember everything — consider using Clocks to track the progress of each Villain’s goals.
The more complex or dramatic objectives will require larger Clocks:
If the Player Characters manage to foil the Villain’s plans, the current Clock will reset to 0 or possibly be replaced with an entirely different one, representing how the antagonist is now seeking to achieve the same end through a different method.
Never create one-dimensional antagonists. Villains should have a deeper layer, a tragic or at least unexpected side to them: perhaps they genuinely think they are doing the world a favor, they have their own reasons for forsaking everyone else, or they feel trapped in a path of ruin and are simply waiting for someone to stop them. Maybe an antagonist is so honorable that they will fully heal the heroes before a battle!
This doesn’t mean the PCs should necessarily sympathize with all Villains — a few will be beyond redemption. But even then, dark emotions must come from somewhere... and upon discovering those tragic roots, Player Characters will see that antagonist under a different light, and perhaps even find a way to help them realize that what they're doing is harmful.