Since it re-rolls every item in the room, it can be more efficient to use it in rooms where multiple items are in the same room. For instance:
In the Shop, when multiple items are available for purchase.
In the Devil Room, when there are multiple deals offered.
In the Boss Room after the Mom fight, where both The Polaroid and The Negative can be rerolled, at the cost of the opportunity to go to the Chest/Dark Room. Once one item is picked up the other will disappear.
In the Angel Room, when there is a choice between multiple items.
In the Boss Rush Room, where all 4 items can be rerolled at once.
With Chaos, every fully depleted item pool will only contain Breakfast.
If Isaac runs out of red hearts in the Devil Room, then rerolls, the prices of the items switch over to soul hearts.
Using the D6 on an active item yields different rerolls depending on whether you picked up the active item first.
Using the D6 to reroll items duplicated with Diplopia will reroll all the items into different items. The copied item will not be rerolled into the same one as the original item.
Be careful when rerolling, as it will replace the item with another item from the current room's item pool, even if the item came from a different pool, or is a set drop. This can be used as an advantage in various ways; for example, after defeating The Fallen, the item will be drawn from the Devil Room item pool, so Isaac can safely roll the item into another from that pool. This behavior can also be an advantage in Angel Rooms since Key Piece 1 and Key Piece 2 can be rerolled to get a free Angel Room item.
Although the D6 is considered a Special Item, it will only count as a special item if found naturally during gameplay. Starting with the D6 as Isaac will not cause fewer special items to appear later on. This fact also extends to Eden's starting items: if Eden starts with a special item, that item will not count toward the special item total.
In the original Binding of Isaac, the D6 had a recharge time of 3 instead of 6.
In the Eternal Edition of the original Binding of Isaac, The D6 has a chance to delete the item instead of rerolling it when playing in hard mode.
The Eternal D6 has the same effect but with a 2 room charge.
In the original Binding of Isaac, this item was called "The Dice".
Like the other dice items, the D6 uses the naming scheme of dice for tabletop RPGs like Dungeons & Dragons, which were associated with devil worship during the Satanic Panic.
The D6 is the only dice item that includes ‘The’ in its name.
This may be because it is ‘The’ quintessential dice item; being the first added to the game, arguably the most iconic, and the only one featured as a starting item - for Isaac himself, no less.
Gallery
3DS The icon of the D6 as seen on the lower 3DS screen.
The D6 is a special item.
Isaac starts with this item once it is unlocked.
Shop, when multiple items are available for purchase.
Devil Room, when there are multiple deals offered.
Boss Room after the 
Mom fight, where both 
The Polaroid and 
The Negative can be rerolled, at the cost of the opportunity to go to the 
Chest/
Dark Room. Once one item is picked up the other will disappear.
Angel Room, when there is a choice between multiple items.
Boss Rush Room, where all 4 items can be rerolled at once.
There's Options or 
More Options spawn two items.
Chests can be rerolled.
Breakfast.
Chaos, every fully depleted item pool will only contain 
If Isaac runs out of red hearts in the 
Diplopia will reroll all the items into different items. The copied item will not be rerolled into the same one as the original item.
The Fallen, the item will be drawn from the Devil Room item pool, so Isaac can safely roll the item into another from that pool. This behavior can also be an advantage in 
Key Piece 1 and 
Key Piece 2 can be rerolled to get a free Angel Room item.
Book of Virtues: Spawns a D6 wisp in the middle ring. An extra wisp is spawned per item rerolled.
Car Battery: Re-rolls twice instantly without any benefits besides doubling the speed of depleting item pools.
Glitched Crown: When the D6 is used, all 5 items will be re-rolled.
Soul of Isaac: Using the D6 re-rolls the current item and cancels alternation.
Eden's starting items: if Eden starts with a special item, that item will not count toward the special item total.
Little C.H.A.D. and 
Little Steven.
Eternal D6 has the same effect but with a 2 room charge.
D7, 
D8, 
D12, 
D20, 
D100, 
Spindown Dice, and 
D infinity has the sides displayed with numbers, while 
D1, 
D4, 
The D6, and the 
Dice 
??? (Character) Unlocks 
Isaac (Boss) Unlocks 
The Binding of Isaac: Rebirth
