Every item has an internal number for its to-hit bonus and an internal number for its damage bonus, even if it's not a weapon. And any item can be wielded, even if it's not a weapon. Most items in the game have these internal fields initialized to 0, but the food ration you start the game with does not. Thus, if you wield your food as a weapon, you will never miss when you swing at a monster, and one hit will instantly kill anything.
To discourage players from descending below dungeon level 26, each level you go down adds 1d8 to every monster's hit dice and 1 point to every monster's armor class. You can use the "wield food" trick to descend VERY deeply into this tomb of horrors, but even a food ration isn't completely invincible. At around level 1000, it starts taking 2 hits to kill a monster. At level 2000, it takes 3 hits. At level 3000, it takes 4 hits. And at around level 3900 or so, you'll start missing and soon won't be able to hit anything at all.
Level 20 was supposed to be the highest experience level your character could attain. So what happens when you drink a potion of raise level when you're at level 20? Your level cycles back down to 1. However, you don't lose any hit points when this happens. You then have the opportunity to gain levels back up to 20 again, and you gain ANOTHER 1d10 hit points with every new level you gain. It's possible to get to level 20, drink a potion of raise level, get back to level 20, drink another potion of raise level, over and over again, beefing your hit points up into the thousands. (Provided you don't get your hit points permanently drained by a vampire in the mean time.)
Once you pick up the Amulet of Yendor on level 26, you are allowed to climb up stairs as well as down them. PC Rogue had to run on a 256K PC with only a floppy drive, so it didn't keep track of what was and was not on any dungeon levels other than the one you were currently on; when you ascended from level 26 to level 25, an entirely new level 25 has to be randomly generated. To prevent you from "level grinding", levels above the lowest level you've visited are devoid of items, so you'd eventually starve to death. However, if you go back down to the lowest level you'd previously visited (e.g. level 26), the level WILL have items on it. Thus, you can go up and down between levels 25 and 26 indefinitely, racking up XP and weapon/armor enchantments until you're a god of sorts.
Saving the game consists of, basically, dumping core to a file. Every variable in the game gets saved and will later be restored, including the random number generator's seed value. This means that for an enterprising gamer who is willing to make copies of the saved-game file, and restore those copies if (s)he died, it's possible to know exactly what will happen next so long as you make exactly the same moves you did the previous time.
In later editions, there was a new feature where throwing a potion could affect a monster — but it also worked when wielding it and when doing so the potion would never break or get used up, making a paralysis potion the most valuable item in the game.
In the Unix version the "identify" scroll was split up into "identify potion", "identify ring, wand, or staff", etc. but every type of identify scroll could identify a staff although the staff was not listed as an item it could be applied to.
When you start a new game, you get to assign your stats. If you minimize your Constitution, you'll get enough points to max out your other stats. If you then pick Magic Arrow as your starting spell, and use it continually, even once you run out of mana, an action that drains your constitution if you do it too much, you will eventually run out of constitution. Normally, this would also cause you to run out of hit points, but for some reason, at level 1 you will stay alive. If you then cast Magic Arrow again, your Constitution will underflow, and roll over to the absolute maximum (which is far above the max you can assign in character creation). Suddenly, you go from having 2 HP to 34. Combined with your other, maxed out stats, you become nearly indestructible.
Watch out for enemies that can drain your stats, including constitution, in the second half of the game. If they drain constitution from you while you're exploiting this bug, you won't be able to have it restored until your current constitution wraps back around and drops below the level you originally set it to.
Shops are implemented in the same interface as your normal inventory, with the shop's inventory replacing the "Floor" inventory. However, if you cast a movement spell (Phase Door, Teleport, etc) while in a shop, the game will glitch slightly, and cause the shop's inventory to appear as a pile of items on the map on the shop's tile. Now, normally you would not be able to access this pile, as the shop appears as soon as you step on to the tile. However, if you use Phase Door to teleport onto the tile, you bypass this, and can now pick up the shop's entire inventory for free, which you can then sell back to him.
If you made sure there were no monsters left on a dungeon map before leaving it, you could Rune of Return and rest/sleep on the village/castle to your heart's content and no new monster would appear in that map. You actually had to return to the map in question and rest/sleep there for new monsters to appear. This was most useful in the final dungeon, but made it less exciting.
In Pokemon Mystery Dungeon, you could completely ignore the "hunger" mechanic in late post-credits quests: only the team leader would ever get hungry, and you could switch out the leader with a teammate anytime you wanted, resetting your belly to 100. This was fixed in the second game by not allowing the switching of the team leader in mid-dungeon, but Gates to Infinity allowed you to switch the team leader again.
In the the expansion set to the second game, Explorers of Sky, a few Joke Items were added that were spelled wrong and meant to be confused with other items. Also added to the game was a "recycling" (item-crafting) feature where you could submit a specified number of arbitrary items and receive a prize ticket for some other awesome items. Thing is, if you submitted any joke items to be traded for a prize ticket, they would not be removed from your inventory if they were selected in a certain pattern, allowing for (almost) free, infinite attempts at the prize booth.
In ADOM, it used to be possible to pick up an unlimited amount of any item if there were enough of them to begin with. When you try to pick up a pile of items that will take you way over your weight limit, the game will ask how many you wish to pick up. It used to be the case that there was no upper limit at this point. So you could start by amassing a huge pile of large rations, seeds gathered with Survival, etc., and pick up even more of them, then sell those until you had so much gold you could do the same thing, and then, well, you could do pretty much whatever you wanted. It was particularly effective for getting enough material to sacrifice to be crowned your god's champion. You just had to be careful not to pick up so much stuff you'll be crushed by the weight of it.
In earlier versions, drakelings' speed would increase without bound when they were affected by heat. Drakeling + fire immunity + temple of elemental fire + time == a base speed as high as you like. This speed would slowly decline once you left the tower, but it was still enough to let you win the game by taking 50 actions for every one NPC action.
Brimsnapping: By rapidly tapping the fire keys when firing a Brimstone shot, you can score up to three more hits, over doubling the damage. This glitch completely breaks if you also pick up Chocolate Milk, however.
Pausing the game at the right time can do strange things. In a Challenge Room, pausing right as you touch the chest or item causes all of the waves to spawn at once, which can be followed up by a use of the Death card or some similar room-clearing attack. With the High Priestess card, pausing at the right time causes the foot stomp to repeat itself. Very devastating considering that this is one of the most damaging attacks in the entire game.
Speaking of The High Priestess, using it in a room with no other non-Mom enemies causes the attack to hit Isaac instead. It also pushes Isaac a significant distance, due to the large hitbox. Far enough, in fact, that it can shove him through doors even if the door isn't open. Even if you can't see the door, like the Devil Room door.
The active use of the Pony item is a charging attack. Upon activating it, you become invincible until you press one of the directional keys to initiate the charge. However, by pressing nothing and instead using the mouse to fire, you keep this invincibility. You cannot re-position, but having homing or Epic Fetus can help address this.
Luck's main effects are influencing drops and the tooth rate of Tough Love. While gaining Luck does give a slight drop boost, due to a math error you can actually gain a larger effect by getting sufficient amounts of negative luck. With sufficient negative Luck, you'll be getting normal chests all the time, giving you tons of collectibles and greatly increasing the Eleventh Hour Superpower effect of The Chest.
Be very careful with Devil Deals at low health. One moment you could be dead while still having soul heartsnote caused by taking the Pact or Mark with only two Heart Containers and no soul hearts. The reduces you to 0 HP and kills you before giving the soul hearts and the next moment you could be taking a deal and surviving with literally no healthnote If you take a deal that puts you into negative max HP, you get hit for a massive amount of damage that should kill you. However, since overkill damage to soul hearts doesn't flow into red hearts, the damage can't quite trigger Critical Existence Failure. The same happens if you're invincible while taking a deal that would put you to zero HP or less, with similar logic to stealing soul heart deals.
The Kamikaze spacebar item turns Isaac into an Action Bomb. However, by pressing against a wall and then using Kamikaze, Isaac doesn't take damage, giving him instantly exploding and spammable bomb attacks as long as his target comes to him. With enough caution, this can also be used to safely blow open doors, including the hidden paths to the Secret and Top Secret Room.