Tips and Tricks from Muffins!

Items:

Polyphemus is a pretty strong passive. While you lose a lot of attack speed, the single tear shots will be able to one or two shot most critters. But the real power comes from combining it with one of the other items that alters your attack. With Mom's Knife or Brimstone you can defeat most bosses in a single blow. This can be a defining factor of your ability to beat the chest.

Also, this works with the Sacret Heart as well, which is great, because the drawbacks of the slower attack speed and shot speed can become a real problem with the homing effect on some mobs. With Mom's Knife or Bromstone however, these issues vanish and both the damage magifiers of both items stack!

Some of the charged items are fairly weak by themselves, but can get much more powerful with the Battery, 9-volt, or the Habit.

The Habit when combined with an item Yum Hearts can extend your total available health by quite a lot! With the Prayer Card you can even gain up to 40+ heart containers if you can gain some Soul Hearts.

With the Book of Shadows and the Habit you will almost be invulnerable to damage.

Also, if you donate to a devil beggar, or blood machine while invulnerable, you won't lose life, but you'll still get the rewards! This also works with the Celtic Cross which procs a shield about a third of the time when you take damage. In both cases, you can really abuse arcades with these items.

So, What do you do if you can't one shot bosses or live forever?

Flies. Juicy, Juicy Flies.

Do not underestimate the power of flies and other orbiting defensive items.

With three such items, you can block a large majority of the attacks you might otherwise be hit by.

In the Chest, I have in one run, stood still and fired straight forward to win the final boss fight. Three flies can just be That strong.

Pills:

Every game, about 6 random pill types are added to the game. Some positive and some negative. Not every type of pill is available in every game.

If you use a pill, the ??? part of the name will be replaced by its effect. However, if you write down the color combo and effect, later in the run you'll be able to tell if buying a pill, with the same colors, in a shop is worth it or not.

If you have the Lucky Foot or PHD, all the pills in the game will become positive in their effects. Or, at least you won't get any effects that make you lose stats.

Secret Rooms:

On every level is a secret room placed to be adjacent to at least two other rooms. If there are multiple 'empty spaces' with 3 or 4 adjacent rooms the secret room could be in any of these spaces. These rooms can have great rewards and either contain: A miniboss (if you're unlucky), A slot machine of either type, 3/6/9 pennies (or some nickles and dimes as every penny is rarely one of these), or an item (if you're really lucky).

Sometimes this room takes you to the Devil/God Room instead.

Also, while we're on the subject, both God and Devil rooms are more likely to appear if you can avoid taking damage during the level and the boss fight. If you have Soul Hearts, I don't believe the game considers you to have taken damage when you lose these.
Also, if you're looking for God Rooms, you can influence the likelyhood that one will by appear by donating to beggars.

Anyhow, you can open secret rooms by placing a bomb directly center on a wall in one of the adjacent rooms.

These secret rooms have their own loot tables compared to treasure rooms. Some of the items can be found elsewhere, but are exceptionally rare.

These rooms can be found if you have a passive item like I Can See Everything, or the Treasure Map, Spelunker Hat, or if you use the Sun tarot.

However the Map and the Sun won't reveal the Ultra Secret rooms.

Most, if not all (past versions have been buggy about this), will also have an Ultra Secret Room. These rooms are found to be adjacent to exactly one room and one room only. These rooms can have a slot machine, a massive amount of hearts, a trinket, a card, a curse room, or contain an Eternal Heart. (White hearts that turn into permanent containers when you leave the level).

Try to avoid looking for these rooms until after you clear the map, as sometimes the location of such rooms will be obvious or greatly narrowed down.

Trinkets:

Never pickup the Tick. Ever. You won't be able to put it back down and it's just not worth it. If you enter a boss room with the Tick, they'll automatically start at 85% of their total health and you'll gain a heart back if you can. So, if you really know what you're doing, go for it. But, if you're trying to get to the Chest, taking the Tick ruins your run. And, prevents you from taking better trinkets.

Picking up Cancer will destroy all your eternal and soul hearts, but it can take your attack speed beyond the stat cap.

The Bloody Penny is pretty abusable in the casino rooms. Donate to the blood machine to get coins, then pick up coins to sometimes get hearts.

Also, donating to the blood machine can leave you invulnerable to damage long enough to donate a second time for free. This especially works in The Womb if you are daring enough.

Sometimes Blood Machines explode and drop either a Blood Bag, which gives you hearts and an a container. Or, an IV.

IVs seem awful at first, as they work like blood machines that will never explode. But, if you activate them at rapid speed by pressing the space bar over and over, you can summon far more coins with the invulnerablity trick then if you were using a real machine.

This can be a good thing, if you like money.

Characters:

Keep Mom's pearl if you're playing as Blue Baby. You'll see more Soul Hearts.

Also, the Photograph once you find it, will trigger everytime the Blue Baby takes damage.

Cain starts with the Lucky Foot, which increases the chances of every rare event in the game. More nickles and dimes, more soul hearts, more items after rooms, no negative pills and much much better odds in gambling.

Cain is kinda powerful. Be sure to unlock him quickly by reaching 55 coins in one playthrough!

Anyhow I hope you've enjoyed or found my tips useful.

Oh, you might be asking about monsters and bosses...

I'll let you figure that part out. : P

Toodles,
Muffins.

P.S. Try not to pick up Eternal Hearts (the white ones), until After you are done with a level. You'll get a lot more heart containers that way!