Iris can best be described as a wallflower. She begins her first day as a temp for the nondescript Global Credit Association by waiting in a chair for two hours. This sets the scene for her (mis)adventures with the other "corporate orphans", Margaret, Paula and Jane. Led by Margaret, they find subtle ways to lessen the ennui of corporate oppression. The tension escalates when the new permanent hire, Cleo, enters the picture.

Three sisters with quite different personalities and lives reunite when Babe, the youngest, has just shot her husband. Oldest sister Lenny takes care of their grandfather and is turning into an old maid. Meg, who aspires to make it in Hollywood as a singer and actress, has had a wild, man-filled life. Their reunion is joyful but also stirs up much tension.

Housewife Roberta Glass of Fort Lee, New Jersey, is feeling restless in her life, where she has not taken any chances, including in her marriage to home spa retailer Gary Glass, who knows what to expect in her every move, and who is more concerned about his public image with respect to his business than her. If being honest, Gary would consider her uptight. She does have a few diversions, one of her favorite being reading the personal classifieds, most specifically those written by someone named Jim whose ads are always titled "Desperately Seeking Susan". Roberta gleans that Jim and Susan are in a relationship of sorts with the ads the only way for him to get in touch with her as she travels around the country. Obsessed with the pair, Roberta decides to go to Battery Park when the latest ad requests Susan meet Jim there. In her sighting from afar, Roberta can see that Susan is a wild, new wavish attired woman, to some extent a polar opposite to Roberta herself. Out of circumstance, Roberta is able to purchase Susan's easily identifiable leather jacket from a third party, which in the process leads to Roberta getting amnesia, further resulting in her being able to obtain all of Susan's personal possessions, making her believe that she must be who these possessions point to her being. This causes some confusion for Dez, a friend of Jim's who has never met Susan, and who Jim, a rock musician, asked to look after Susan in his needed absence out of town for a gig. Dez, a movie projectionist, can't help but fall for Roberta who he believes is Susan, while Roberta, in her newfound freedom, falls for Dez in return. What Roberta is unaware of, even before her amnesia, is that a criminal, Wayne Nolan, who has already killed once, is after Susan with regard to some priceless Egyptian earrings Susan has out of circumstance, he only knowing her from that iconic leather jacket. Susan does eventually learn this information about Wayne and thus tries to track down this mysterious woman who has stolen her possessions both to get back her stuff but also warn her about Wayne. Matters will only get more complicated as Gary gets closer to tracking down his missing wife, when Jim comes back into town looking for Susan, and if and when Roberta regains her memory.

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