After trying a few insane solo poverty and no reload runs, and after having learned of an exploit with my already-favorite wand, the Wand of Lightning, I am considering doing a new run of BG2 (I have the original only, not EE) without resting, from Chateau Irenicus to the Throne of Bhaal. A poster asked if this was feasible in a much older thread, and I believe it could be done fairly easily.
The Wand of Lightning trick, which will likely be a big part of this run, involves targeting 6 enemies with the wand (its normal behavior; it fires off 6 tiny bolts instead of one big one) and then replacing the wand's quick item slot with another item, such as a scroll of Magic Missile, a Potion of Healing, or a Wand of Cloudkill. We would then use that replacement item 6 times: casting 6 Magic Missile spells in one round, one after another at normal speed; drinking the potion 6 times for 54 HP healed; or dealing 6d10 poison damage per round for 10 rounds. If we select multiple targets with the Wand of Lightning, the replacement item will target them instead: a Wand of Paralyzation could hit 6 enemies instead of 1.
Another possibility is a sneaky way of avoiding fatigue, which I have yet to test: instead of dragging around a party of fatigued NPCs, I will kill all or most of them after each major battle, and resurrect them before the next. They should still steadily accumulate fatigue, which may weaken them enough to warrant switching them out for new NPCs. An alternative would be removing them from the party whenever I don't need them, but this would be much more inconvenient and could not be done between Spellhold and returning to Athkatla. In either case, the main character would still have massive penalties to luck, be unable to hit non-disabled enemies, and would suffer maximum enemy spell damage every time.
There are more tricks that could actually make the run even easier (for instance, casting Nahal's Reckless Dweomer via a hotkey without expending a spell slot), but I will try to minimize the use of exploits, and see how few are needed to get through the game. The Wand of Cloudkill could end almost any encounter (33 average damage per round, for 10 rounds, bypassing spell protections?), so I will try to vary my game and see how many different ways I can get by without resting. Nuking everything with wands would get tedious.
I am considering using a mage dual-classed to a thief. The mage levels will let me use wands when the rest of the party is dead (Aerie can use wands for me while I'm regaining my mage levels), and the thief levels will give me a few one-time uses of traps. Later in the game, I will have UAI and can boost my MR to 100, negating the fatigue penalty for incoming spell damage. A bard could serve much the same purpose. Other builds would either rely on weapons they couldn't use or spells they couldn't memorize, which is what I have other party members for. If fatigue penalties apply to thieving skills, however, all thieving skills would quickly become impossible, and only a bard could apply HLA traps.