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在中美戰爭期間, 唯一倖存者結婚了， 有一名兒子肖恩, 購買了巧手先生嘎抓。 在2077年的10月23日，独存者/奈特正在准备康科德老兵纪念馆的演讲时，一个避难所代表拜访了独存者的家并要求他填写111避难所的进入申请表。不久之后，新闻播报员便播报了美国遭受核打击的新闻，独存者一家被迫冲向111避难所，在被科学家净化后，他们一家便被封在了冬眠仓里，从2077到2287，独存者始终处于神志不清的状态。
The player character heads home to Sanctuary Hills, now ruined from the bomb blast, where they meet a distraught Codsworth, revealing to the Survivor that over 210 years have passed since they were frozen in the Vault, also telling the player character to go to Concord for help. The Sole Survivor then meets Preston Garvey - one of the last of the Commonwealth Minutemen - and assists him in protecting settlers from a group of raiders and a Deathclaw, later helping them to travel to, and settle into the remains of Sanctuary.
After helping Garvey and his group, the player is instructed to go to Diamond City, a settlement based in Fenway Park where they meet Piper Wright, the city's reporter, who tells the player character to seek out the city's detective Nick Valentine who is revealed to have been missing two weeks prior to the Sole Survivor's arrival in Diamond City. After finding Valentine, they learn the identity and location of their spouse's killer, a man named Conrad Kellogg. Tracking him down, Kellogg reveals that Shaun is in The Institute, a secretive organization feared by the people of the Commonwealth, that is based below the ruins of the Commonwealth Institute of Technology. The player then kill Kellogg and retrieves a cybernetic implant from his brain. After some consultation with Nick and Piper, they head to Goodneighbor where they first encounter John Hancock, the self-appointed ghoul mayor of the town, and get help from Doctor Amari, a scientist skilled in neuroscience. The doctor assists the Sole Survivor in viewing the dead mercenary's memories and discovering that the Institute uses teleportation as the means of travel between their facility and the surface. During their hunt for Kellogg, the Survivor also witnesses the arrival of the Brotherhood of Steel in an airship called The Prydwen, their mobile airship HQ.
After viewing Kellogg's memories, the player is then tasked to go to the Glowing Sea - the ground zero of the nuclear blast during the intro sequence - to find Brian Virgil, an ex-Institute scientist specialized in researching the FEV virus, who has escaped and went into hiding, to get help in infiltrating the shadowy organization. Virgil, now mutated into a super mutant by prolonged FEV exposure, mentions that the player must kill an Institute Courser - one of the most advanced creations of the Institute, designed to be stronger, faster and smarter than average human beings - to get a special chip from it in order to access the Institute. Once the chip is retrieved, the player is directed to find The Railroad, a secret organization that works to free synths from the Institute's control and give them normal lives in the Commonwealth, since only one of its members, Tinker Tom, can decode the chip and get the frequency code used by the Institute to teleport.
The player then heads back to Virgil, who gives them a blueprint of a device that hijacks the frequency of the Institute's Molecular Relay. After retrieving the blueprints, the player must seeks assistance from one of the three factions: the Minutemen, Railroad, or the Brotherhood. Once the device is built, the player infiltrates the Institute to find their son.
After finding a synth based on a young Shaun, it is revealed that the real Shaun was kidnapped in 2227, sixty years prior to the Survivor's release from cryogenic sleep,垂垂老矣的尚恩，已经成为学院的理事, entitled Father。
独存者将面临一个决定联邦命运的选择:从剩下的三个势力里选一个与学院进行对抗。铁路会摧毁学院，解放合成人，兄弟会会毁灭所有合成人与学院，义勇军则会出于保护联邦摧毁学院(and the Brotherhood of Steel if made hostile to the player) 。当然，玩家也可以选择帮助尚恩摧毁铁路与兄弟会（义勇军可以说服加入）。任何一个选项都会导致尚恩的死亡，可能是由于他的癌症，也有可能是独存者亲自动手。
- 這是Fallout series系列遊戲中第一個完全配音的玩家角色 。
- In a departure from previous games, character customization is done without slider options. During the opening portion of the game, the character stands in front of a mirror and alters facial features using a cursor. While making changes, the spouse stands behind the Sole Survivor and makes comments about the alterations.如果玩家決定變性，角色的配偶就會走到鏡子前。
- Codsworth can refer to the player character by name as Bethesda has recorded over 1000 popular names for use in-game. This includes both real names and joke names. A list of names can be found here.
- The Sole Survivor has the option to romance many of their human companions, except Deacon. In addition, the Survivor may romance some synths, such as Curie and Danse, and the ghoul Hancock.
- The default character build for male Survivor is called Nate, and female called Nora.
- The Sole Survivor is the first player character to have lived in the Pre-War era.
- Prior to the release of the game, the universal default name for the male Sole Survivor was Mr. Howard. This was due to Bethesda Softworks director Todd Howard using this name during Bethesda's first E3 presentation.
- 儘管官方給主角的稱號是獨存者(Sole Survivor)，但遊戲中普遍出現對你的稱呼只有一個，即避難所居民(Vault Dweller)。However, they do sometimes call themselves the "only survivor", notably while in Vault 81.
- If one lets Desdemona pick a Railroad code name for the Sole Survivor, her choice will be "Wanderer", a possible reference to the Lone Wanderer of Fallout 3, or the song "The Wanderer", played on Diamond City Radio.
- 在開局時如和狗食碗對話, 唯一倖存者會感嘆 "狗就這麼丟了", 證明在 Great War 前他們曾經養狗。
- 和配偶之間的對話暗示尚恩是在公園做愛懷上的。 When Nate suggests going to the park, Nora's sarcastic response option is, "Oh, right. The Park. With you. Because I want to get pregnant AGAIN."
- Interestingly, if one skips dialogue during conversations they may hear the Survivor mumble sarcastic comments about the NPC they are talking to instead of just "mmmh" and "alright"-for example they might say "Nice hat" when talking to Nick Valentine, "Minutemen, jesus" when talking to Preston Garvey or "Ugh, old people" when talking to Mama Murphy.
- .玩家的性别可能会有不同的对话，比如在某处与普雷斯顿·加维对话时加维会说“好傢伙(guy)!”，女性角色会有一个选项: “嗯……我不知道怎么和你解释，但我不是一個傢伙(a guy)”
The Sole Survivor appears only in Fallout 4.