Look, as a gamer, I'm mostly Rules Lite, even when using crunchier systems, but I'm also a big fan of the one-off mechanic. So let's talk about Fatigue.
Fatigue is something that certainly occurs in real life - this article is inspired by my having over-stretched myself this week with the podcast side of things (8 episodes of SOMEthing in as many days) - and should be happening to characters in role-playing games. So much of adventure gaming is about WALKING, you'd think the PCs would be dead tired all the damn time. And that should be a drain on their stats.
But calculating fatigue and its attrition on your attributes isn't just a pain in the ass, it's boring. It's real-life, not heroic. If you even remember to do it. It forces you to think about rest, and then role-play "resting". It's about all the stuff they cut out of the movie, y'know? So whether because of exertion, encumbrance or wounds, I'm sure most players and GameMasters ignore this element even when the game has a mechanic for it (unless it's so integrated into the rules as to be unavoidable - as with a token/dice pool trade system with a cost for every tiring action).
And that's fine. There's no real need for it unless it's the actual focus of the adventure. Ah! But what if it IS the focus of the adventure? I think that's where I would want to bring the Fatigue (or other attrition) mechanic front and center. For example, the scenario is specifically about having to pick up and move small heavy objects up a mountain fraught with danger. Or you're on a barely Class-M planet with a thin atmosphere. Or those Elder Gods are psychically screaming in your head, but you don't quite notice it's happening, just that you feel like you're in a fog. That time-bomb poison you drank - or your failing battery, Robot-Boy! - will kill you unless you get to the one person who can help you.
In those cases, a mechanic you'd rather ignore normally because the whole THEME of the adventure! It's a way to make an environment have a different feel! Increase the tension! Ah yes, now I want to use Fatigue. But it's got to be a special occasion.
If your game doesn't have a fatigue mechanic already, it's simple enough to craft one. Give each player tokens/points to spend that represent adrenalin. It's nature's energy drink. They can stave off fatigue which might be equal to hit points or some appropriate number. Attrition occurs when you're at half strength, quarter strength, and dead tired, when the character finally succumbs... passes out? Gets that nasty cold he or she's been holding off by sheer force of will? Worse? Depends on the circumstances.
By making Fatigue central to the STORY, the mechanic goes from dull to intense, a kind of ticking clock on your character's health and energy level, instead of another accounting task to blunt your pencils on.
Perhaps there are other mechanics like this...?