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　　故事延续第三季精采的剧情。西雅图恩典医院因为这些实习医生之间的爱恨情仇，变得更加热闹更有可看性！
　　第三季中格蕾终於摆脱了德瑞克和兽医间的三角恋情，依自己的心意选择了所爱的人。伊兹在丹尼死后一厥不振，甚至想要放弃成为外科医生的梦想。克莉丝汀知道了柏克的秘密后，一直企图帮他掩饰。而乔治和性感火辣的住院医师之间的关係变得更迷离。而艾立克斯竟发现自己还是爱著伊兹！另外，马克为了艾蒂森竟也来到了西雅图恩典医院工作。
　　Meredith和Cristina蜜月归来（买好的机票不好浪费~），Burke已经消失无踪。去年的实习医生Meredith, Cristina, Izzie和Alex，已经获得了正式驻院医生的资格，并且有了自己的跟班，一群初出茅庐，青涩而稚嫩的实习医生。当中，有去年考试不及格的George，还有Meredith素未谋面的妹妹Lexie Grey。今天，他们将要处理一宗三车连环相撞的交通意外，大量的伤者让新来的实习手足无措，目瞪口呆。另一边厢，Derek和Meredith的感情陷入僵局，有可能他们都会和新来的同事有新的感情发展。Bailey对于Callie成为驻院总医生感到气愤，也许她一时三刻还难以接受自己现在要向Callie汇报工作。Richard留任外科主任，仍然是大家的老大~(简介转自YDY)
　　After failing his exam, George reluctantly faces his first day reliving his internship among a sea of fresh faces. Meanwhile, Cristina, Meredith, Izzie and Alex are in charge of their own interns and George is assigned to Meredith.
　　Neither Cristina or Meredith have heard from her exes since the wedding, and they don't seem overly concerned, which astounds Izzie, who is counting every day since she last spoke to George. George asks to talk to Meredith but before he can get her alone, the rest of the new interns show up in the hall and are shooed off by the residents. George gives up and joins the interns. Cristina nicknames him "Bambi," saying he needs to learn how to deal with his new situation.

　　泰德（乔什·拉德诺 Josh Radnor 饰）和罗宾（寇碧·史莫德斯 Cobie Smulders 饰）经历了多番波折后在一起，却因为罗宾害怕结婚而分手告终。因为这段感情的结束，泰德恢复了昔日的单身汉生活，罗宾则去了阿根廷散心。然而当罗宾回到纽约时，她带回了一个帅气的男朋友凯伊，这让泰德大受打击。花花公子巴尼（尼尔·帕特里克·哈里斯 Neil Patrick Harris 饰）热衷于物色漂亮女孩发展一夜情，他对于泰德恢复单身感到相当兴奋，他怂恿泰德再次成为他的“最佳伙伴”。泰德何时才能遇到他的真命天女？
　　婚后的马修（杰森·席格尔 Jason Segel 饰）和莉莉（艾丽森·汉妮根 Alyson Hannigan 饰）决定搬出和泰德合租的公寓，二人用尽积蓄买下一套新房，却发现房子是歪的。虽然他们的生活偶尔有磕磕碰碰，但是小两口的日子总体过得十分美满幸福。

In 2262, Earthforce Captain Elizabeth Lochley is appointed to command Babylon 5. The station grows in its role as a sanctuary for rogue telepaths running from the Psi Corps, resulting in conflict. G'Kar, former Narn ambassador to Babylon 5, becomes unwillingly a spiritual icon after a book is published that he wrote while incarcerated during the Narn-Centauri War. The Drakh, former allies of the Shadows who remained in the galaxy, take control of Regent Virini on Centauri Prime through a parasitic creature called a Keeper, then incite a war between the Centauri and the Interstellar Alliance, in order to isolate the Centauri from the Alliance and gain a malleable homeworld for themselves.                                    
                               　　Centauri Prime is devastated by Narn and Drazi warships and Londo Mollari becomes emperor, accepting a Drakh Keeper under threat of the complete nuclear destruction of the planet. (Portions of the end of his reign are seen in various prescient visions throughout the series; they show Mollari and former nemesis (and later friend) G'Kar sixteen years in the future dying at each other's throats, seemingly out of their grudge. It is gradually revealed that there was a much more friendly subtext, with Mollari having become a slave to the drakh rule and being tired of life; his Drakh Keeper awakens and strangles G'Kar in return. Vir Cotto, Mollari's loyal and more moral aide, succeeds him as emperor, free of Drakh influence. Sheridan and Delenn marry and move to Minbar, along with the headquarters of the Interstellar Alliance. G'Kar leaves Babylon 5 to escape his unwanted fame and explore the rim. Garibaldi also marries and settles down on Mars. Most of the other main characters leave B5.                                    
                               　　Nineteen years later on the verge of death, Sheridan takes a final trip to the obsolete Babylon 5 station before its decommissioning. Sheridan apparently dies but is claimed by the First Ones, who invite him to join them on a journey beyond the rim of the galaxy. Babylon 5 station is destroyed in a demolition shortly after Sheridan's departure, its existence no longer necessary as the Alliance has taken over its diplomatic purposes. This final episode features a cameo by Straczynski as the technician who switches off the lights before Babylon 5 is demolished.