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Ultra Mutant Overview
Ultra Mutant is the rarest achievement in the game. While this achievement will pose some challenges, a large part of the rarity is due to how many repetitive unlocks are needed. This achievement is NOT about unlocking every other achievement, it is about getting the unlock counter in the stats menu to 100%. These include getting all 12 characters unlocked, all 12 b-skin unlocks and by extension a golden weapon on each, and every crown unlock on each character which is a total of 144 crowns.
Secret characters are NOT required for Ultra Mutant, they can technically unlock crowns but not required. Golden Nuke Launcher and Golden Disc Gun are tied to the Good Riddance achievement but not required here, they just count as any other golden weapon. Hardmode will be required to unlock in order to get Chicken's B-Skin, however.
As there are a lot of crowns it's easy to forget what is unlocked along the way. For that reason a tracker can be found here, though requires a google account to make a copy.
B-Skins & Golden Weapons
Many of these unlocks will be gotten before the grind for Ultra Mutant even begins, and the rest can be done during the crown grind. There are a few to keep an eye out on:
Melting's B-Skin is a particularly difficult, there will be an entire guide dedicated to this later.
Chicken's B-Skin will seem difficult to those unfamiliar to hardmode, however is doable to anyone who's also able to get Hardmode. One of the best strategies is to run Golden Grenade Launcher + Crown of Death as it lets her kill any tanky enemies (Elite IDPD, Flies, Big Bandits) with ease due to the bonus damage.
YV'S B-Skin should come naturally as the game is progressed. However if RNG becomes too annoying at any point, one character can store their golden weapon in a Proto Chest that another character can pick up in a following run.
The most efficient use of time is to constantly be unlocking crowns for runs that include B-Skin attempts, though runs around specific crown unlocks may need full focus on them.
Crown Unlocks
All 12 characters need to unlock all 12 crowns which totals 144 crown unlocks needed. This includes 72 preloop crowns and 72 loop crowns, the most efficient way of unlocking these would be to go for both a preloop and loop crown unlock at the same time.
Crowns can be unlocked through three methods - sitting on the Throne, entering the loop portal or sitting on Captain's chair. The quickest of these methods would be to unlock a preloop crown by entering the loop portal, taking a crown in the 1-2 L1 vault, and then entering HQ immediately. While HQ is a particularly difficult area, Captain can become easier to handle with experience. This will be expanded upon later, but melee is particularly useful for this fight as her orbs can be deflected right back into her face.
Another popular strategy is to take the vault on 7-2 L1 and then immediately do the Throne fight, as it largely avoids the downside of the crown. Be aware that visiting 3 Crown Vaults in a run causes them to no longer spawn if doing this strategy.
Dailies and Weeklies both allow for crown unlocks. There is a community scouting sheet that can be used to plan out routes, which could be used for more difficult crowns. If a weekly has a loop crown for its loadout, that can be unlocked in preloop.
A full guide on crowns can be found here. This page includes tech for every single crown and strategy guides for them, which gives any useful tips and explains what mutants are easier/more difficult to unlock.