Bethany is unable to utilize Soul Hearts and Black Hearts as health. When picked up, they instead are converted to a resource unique to Bethany called "soul charges" at the rate of one charge per half heart. The number of soul charges currently owned is listed along with the pickup counters. Soul charges can be consumed to use Bethany's activated item when the item isn't fully charged, at the rate of one soul charge per empty bar of charge.
Bethany's Book of Virtues starting item, combined with her unique soul and black heart usage, means that she is a character who sees significantly more Angel Deals than other characters – but at the expense of generally requiring beating floors without taking damage to do so.
Since Bethany can't use soul and black hearts as a buffer, Angel and Devil Deals are much harder to get. This will usually mean beating floors without taking damage.
Ways to allow Bethany to protect her devil deal chances include picking up an eternal, rotten, or bone heart.
It's recommended to maintain a large amount of wisps from the Book of Virtues to keep up a barrier around Bethany, protecting her from taking damage (and thus losing out on a Deal).
Devil Deals are riskier to take – reducing the red heart count leaves Bethany more vulnerable than other characters.
An Angel Room will always spawn as Bethany's first deal room due to her starting item, the Book of Virtues.
The item also means that Bethany will continue to have a chance to spawn more Angel Rooms even if she takes a Devil Deal later on.
However, this also means that Book of Virtues will not be removed when turned into a different character with items such as Clicker or Ankh.
Bethany's intrinsic soul charge mechanic is, while almost always seen with Book of Virtues, entirely separate from it. In the rare event that the book is lost, she can still spend soul charges to use whatever applicable active item she has.
Book of Shadows: Using the Book of Shadows will render Bethany as well as her wisps invulnerable, making it easier to stack up on wisps, while also transforming them into a very effective source of damage, as Bethany can freely ram every enemy in a single room without the wisps dying. A secondary positive is that soul charge makes it possible to activate the invulnerability at will, making it easier to complete a whole floor without taking damage.
Car Battery: Doubles the wisps generated from activating Book of Virtues, allowing many wisps to be generated quickly.
Glass Cannon: If broken, can be fixed instantly with soul charges. Can also be used to generate high-damage wisps while outside of combat.
Glyph of Balance: Will produce soul hearts every room clear when Bethany has more than 5 bombs, 5 keys, a trinket, less than 6 total Red Heart containers of any kind, and full health. This allows you to stack up hundreds of soul charges.
Gnawed Leaf: As Bethany turns invincible, so do her wisps.
Lodestone: The wisps' tears are attracted to the magnetic enemy, making it much easier to connect all of the wisps' tears on an enemy.
Monstro's Tooth: Spawns a wisp that looks like a tooth. These wisps shoot teeth, 50% slower than the average wisp, but deal 12 damage per shot.
Prayer Card: Prayer Card is immensely helpful to build up health, and can be fueled with soul charges to accomplish this even faster. Wisps created by this item also have homing tears and increased damage, similar to Sacred Heart.
Schoolbag: Allows carrying two active items, increasing the rate of wisp generation.
Shoop Da Whoop!: In addition to regular effects, spawn an orbital. When used again, all orbitals spawned by this item will share this effect with main character. Since the amount of this type of wisp is not limited, it will be a good damage dealer.
Spin to Win: Creates a ring of Wisps every 3 seconds that provide a lot of protection and high DPS. However, Spin to Win wisps cannot be retained between uses.
Tear Detonator: If you are willing to wait a few minutes for it to repeatedly regenerate its single charge, it is possible to always have eight orbitals at the start of each room with no resource expenditure. Better still, spamming the detonator while firing results in a tremendous amount of carnage in exchange for a single soul charge per button press. This is especially helpful in Greed / Greedier mode, as each wave fully recharges it. Be careful, however, as spamming the detonator too aggressively may crash the game.
Unicorn Stump: While the item is active, the wisps become invincible and continue to deal contact damage, creating an effect similar to My Little Unicorn, but with only a one-room recharge, allowing you to use it in every room, or even multiple times per room through use of soul charges allowing for near permanent invincibility.
Urn of Souls: A no-cost, spammable item capable of keeping the wisp count maxed out. Additionally, the wisps spawned may shoot tiny The Candle-like flames capable of blocking shots.
Vibrant Bulb Works with items that are fully charged with soul charges even if it's not completely full from room charges.
Yum Heart: As Bethany relies on red hearts to stay alive, Yum Heart can be very valuable and can be fueled with stockpiled soul charges when necessary.
Spin to Win: With the Book of Virtues you can get many shooting fire-orbs in a short time. Spin to win will autoload itself so you can use it fast again.
Conceptually, Bethany first began as the main character for a game envisioned by developer Kilburn as a college research project, originally named "Dora". She was added to The Binding of Isaac: Antibirth (the fan creation that would later become Repentance) after Kilburn deduced that she wouldn't be out of place  in the game.
Her name is a reference to Mary of Bethany. She was the sister of Lazarus, and is sometimes identified as Mary Magdalene or as an anonymous sinful woman in the Gospel of Luke.
Bethany, the village Mary lived in, was a town in the West Bank of Jerusalem. Martha and Lazarus likewise lived there, and the raising of Lazarus from the dead occurred there as well.