G'day
I don't think that there could be a single setting that would do all and be all for me, because I like to vary genres from game to game. Some campaigns are hard SF, some are Space opera, some are near future, some are historical, some are contemporary, some are high fantasy, some are fantasy tropes on historical settings.
The game system that could do all and be all for me would have to be able to handle all those different genres without problems, and it would need to cover chase sequences, social interaction, stealth, shadowing, infiltration and patrolling, seduction, persuasion, dissimulation, fire combat, melee combat, sacerdotal magic, thaumaturgical magic, and animistic magic, some kung-fu-movie ch'i abilities and mystical disciplines, climbing, spaceship combat, and a whole bunch of other things like that, not just combat, and preferrably all with a single resolution mechanic. I find that ForeSight (together with its fantasy supplement HindSight) just about fits the bill. That is the game I play most often, though I sometimes wander off to try something else, or use eg. 'RuneQuest' for a special purpose.
Regards,
Agback