Instructions
Progress through the game. Not only do possible loot drops get better as the game progresses, but there are more changes the longer the game is played and the level of the weapons increases as the level of the character does.
Maximize loot opportunities by completing quests, going on explorations, randomly pillaging, and opening boxes -- these all offer an equal chance of unveiling an absolute gem of an item. Uncover as much as possible, which is the best way to raise your chance of getting the great loot available. While the loot is always random, one thousand chances with a random generator is better than one hundred chances.
Inspect the items available from Marcus and Dr. Zed's vending machines throughout the game. Check with them whenever possible. Occasionally the vendors offer a valuable piece of loot.
Save the game before opening any of the free treasure boxes scattered around the planet. Open the box after saving. Reset the game and open the box again if you do not like the item. Continue to restart and reopen until you receive something nice, as the random loot generator changes the item every time. Save the game after getting what you want and move on.
Hunt the strongest monsters; strong monsters means strong loot. Bosses like Crawmerax, included in the "Secret Armory of General Knoxx" expansion, routinely drop some of the best items in the game.