在上季最后一集中，John Slattery（饰演Victor Lang）迎娶了Eva Longoria所饰演的Gabrielle。但是，在之后的采访中John说过，他在剧中露面的时日不会太多了。这就意味着一出大戏将要上演。而这场戏肯定同Ricardo Antonio Chavira所饰演的Gabby的前夫Carlos有很大关系。来自加拿大的喜剧明星Nathan Fillion在新季中将扮演一位新搬入的妇科医生。另外，一对男同性恋伴侣也将是新的角色。他们的加入，也将为本剧增加更多喜剧色彩。
- Susan Mayer – Susan开始与她的医生Adam Mayfair约会，后来发现Adam有一个与他的前妻Katherine有关的神秘黑暗秘密。Susan面临财务困境，不得不搬出她的家。她对自己变老感到不安。
- Bree Van de Kamp – 为了掩盖她的女儿Danielle的怀孕而假装自己怀孕。她努力应对丈夫Orson的酗酒问题和与一名脱衣舞娘的婚外情。尽管一片混乱，她仍然试图维护她完美的家庭。
- Gabrielle Solis – 在生下第二个女儿后逐渐适应母亲的角色。后来，她被维克多（一位成功的政治家，竞选纽约州州长）的奢华生活所吸引，并同意嫁给他，尽管对她的前夫Carlos仍有情感。在与维克多结婚期间，她与前夫Carlos发生了一段婚外情，引发了两人生活中的复杂问题。
- Lynette Scavo – 被诊断出患有癌症，但没有告诉家人。她努力维持超级妈妈的角色，同时秘密与疾病作斗争。她担心她的病情会如何影响家庭。
- Edie Britt – 返回Wisteria Lane并在主妇们之间制造麻烦。与Katherine的前夫Mike展开一段婚外情。在输给Susan后，她寻求报复。
对紫藤街来说，平静的表面之下其实暗潮涌动。《绝望家庭主妇》第四季的故事是从Mary Alice Young为了掩盖一个惊天秘密而自杀身亡开始的。在每一集中，她都会以逝者的身份，从局外人的角度，用旁白的方式讲述朋友的生活。这也是本剧制作上的亮点之一。她的朋友包括：Susan Mayer，一位在爱情的旅途上坎坷不断的离异单身母亲；Lynette Scavo，被事业和家庭搞得焦头烂额的母亲；Bree Van De Kamp，养有两个问题小孩的寡妇；Gabielle Solis，曾做过当红模特的她，拥有很多女人们梦寐以求的东西——富有的丈夫、豪宅、香车，但美满的婚姻却不肯眷顾她。还有一位多次离婚的Edie Britt，地产经济人，她的爱情生活也是一团糟。
Susan Mayer – Starts dating her doctor Adam Mayfair, who ends up having a mysterious dark secret related to his ex-wife Katherine. Susan deals with financial troubles and has to move out of her home. She feels insecure about growing older.
Bree Van de Kamp – Pretends to be pregnant to cover up her daughter Danielle’s pregnancy. Struggles to deal with her husband Orson’s drinking problem and affair with a stripper. Tries to maintain her perfect household despite the chaos.
Gabrielle Solis – Adjusts to motherhood after having her second daughter. Then she gets swept up in Victor（A successful politician who runs for governor of New York）’s lavish lifestyle and agrees to marry him, despite still having lingering feelings for her ex-husband Carlos. While she was married to Victor, she has an affair with her ex-husband Carlos, leading to complications in both their lives.
Lynette Scavo – Diagnosed with cancer but hides it from her family. Struggles to maintain her supermom role while battling the disease in secret. Worries how her illness will impact her family.
Edie Britt – Returns to Wisteria Lane and stirs up trouble amongst the housewives. Embarks on an affair with Katherine’s ex-husband Mike. Seeks revenge against Susan after losing Mike to her.
Apart from the main actors and actress, here are some of the notable new supporting actors introduced in Season 4 of Desperate Housewives:
- Gale Harold plays Jackson Braddock – Susan’s new love interest, a southern artist who paints portraits of her. Their romance is short-lived.
- Neal McDonough plays Dave Williams – A mysterious new neighbor on Wisteria Lane who is later revealed to have a dark connection to Mike Delfino’s past.
- Kendall Applegate plays Penny Scavo – Lynette and Tom’s previously unknown daughter from his college affair, who arrives unexpectedly to live with them.
- Madison De La Garza plays Juanita Solis – Gabrielle and Carlos’ daughter, who Gabrielle struggles to bond with as a new mother.
- Valerie Mahaffey plays Helen Rowland – Kayla’s mother who tries to extort money from Tom by revealing his past affair and love child Penny.
- John Slattery plays Victor Lang – Gabrielle’s fiance then husband, a politician who runs for governor of New York.
- Rachel Fox plays Kayla Scavo – Tom’s illegitimate daughter who comes to live with the Scavo family and causes problems.
Polly Bergen plays Stella Wingfield – Lynette’s cranky, interfering mother who comes to visit her, annoying Lynette.
Gale Harold 饰演 Jackson Braddock – Susan的新恋情对象，一位南方艺术家，为她画肖像画。他们的恋情很短暂。
- Neal McDonough 饰演 Dave Williams – Wisteria Lane上的一位神秘新邻居，后来揭示出与Mike Delfino过去有着黑暗联系。
- Kendall Applegate 饰演 Penny Scavo – Lynette和Tom的先前不为人知的女儿，是Tom大学时期外遇的结果，她意外地来到他们家居住。
- Madison De La Garza 饰演 Juanita Solis – Gabrielle和Carlos的女儿，Gabrielle在新当妈妈时努力与她建立亲子关系。
- Valerie Mahaffey 饰演 Helen Rowland – Kayla的母亲，试图通过揭露Tom的过去外遇和私生子Penny来敲诈他的钱财。
- John Slattery 饰演 Victor Lang – Gabrielle的未婚夫，后来成为她的丈夫，一位竞选纽约州州长的政治家。
- Rachel Fox 饰演 Kayla Scavo – Tom的非婚生女儿，来到Scavo家庭居住并引发问题。
- Polly Bergen 饰演 Stella Wingfield – Lynette讨厌的，碍手碍脚的母亲，来拜访她，令Lynette感到恼火。
