Your main choices early on are whether you want an earth-like sim or not. Then if you want outer planets for extra challenge or not. Then if you want life support (it makes midgame->endgame a nightmare). Then finally if you want game breaking endgame tech, like alcubierre drive and so on.

I'd recommend no life support, outer planets, no hardcore sim like realfuels/nuclear reactor propulsion/kerbin resizers etc and breaking endgame tech (like EPL).

Required mods for me: kis/kas if you like building & eva, vanilla+ part packs, scatterer, [x]science, atmosphereautopilot(if you dont like mechjeb's autopilot), CRP, distant object enhancement, dynamicbatterystorage, mechjeb, nearfuture* except nuclear, science-full-reward

texturereplaced and TUFX if you're into eye candy