A Hoboken parishioner recently promised to donate $10,000 if the Sisters went to Las Vegas to perform in a friend's showroom. Though Reverend Mother had serious doubts about appearing in Sin City, the Sisters convinced her that "what happens in Vegas stays in Vegas."
The Sisters begin by visiting with the audience and taking names of people who want to participate in a game later in the show. They introduce Reverend Mother, and the "real show" begins: the Overture plays and, in a "Vegas-style" pageant, the cast is presented. An announcer reads brief bios of each of the Sisters: Reverend Mother Mary Regina, Sister Mary Hubert, Sister Robert Anne, Sister Mary Paul (Amnesia) and Sister Mary Leo. They all sing the opening ("Life Is a Game of Chance").
Sister Robert Anne voices her concern that the audience may be expecting some "T. and A." Reverend Mother says they'll give the audience plenty of T. and A. - talent and attitude. "T. & A." becomes a Chorus Line- style production featuring all of the nuns. This is followed by "The Shtick," a quick vaudeville routine of comic one-liners.
Knowing the audience has come to Las Vegas to gamble, Sister Amnesia hosts a game of "Holy Rollers," consisting of a giant slot machine featuring pictures of the virtues that she has chosen: Faith, Hope, Charity, Will and Grace. Participants can win prizes if they spin the right combinations. After hearing some questionable conversation from Sister Amnesia, Reverend Mother reiterates her concern about the Sisters appearing in "Sin City." Sister Hubert answers her in the duet "What Plays in Vegas."
Sister Hubert then explains to the crowd that Sister Amnesia's puppet, Sister Mary Annette, manages to appear in every show, much to the chagrin of Reverend Mother. Rather than fight the inevitable, Reverend Mother decides to "get it over with" and invites Sister Amnesia and Sister Mary Annette to the stage to perform "The Ettes." But Sister Mary Annette is missing, and Sister Amnesia firmly believes she has been stolen. Sister Hubert sends Amnesia off to look for her.
Sister Mary Leo presents a solo number in which she demonstrates her talent at various dance styles ("From Vaudeville to Vegas"). She complains to Sister Hubert that she is having a terrible time as a "nun ballerina" because Reverend Mother insists that she wear the traditional habit at all times. Sister Hubert tries to cheer her up with a 50's rock song ("When the Chips Are Down").
Reverend Mother returns to the stage with a story of her past and admits that she once danced in a burlesque show. In her dream, the Sisters recreate Reverend Mother's appearance. Sister Amnesia returns from her search just in time for the number ("The Fifth From the Right"). When the piece concludes and Reverend Mother leaves the stage, Sister Amnesia confesses she has been in the casino (forbidden by Reverend Mother) and has won a bundle of cash. She thinks Sister Mary Annette may have been kidnapped and will require a ransom ("What's Black and White with Her Money on Red?") Sister Robert Anne tells her to hide the money in the dressing room.
The act ends with all of the Sisters participating in a musical version of the Hindenburg as envisioned by Cirque du Soleil. ("Cirque du Blimp"/"Life Is a Game of Chance" Reprise).
After an Entr'acte and a short reprise of "Life Is a Game of Chance," Sister Leo tells Robert Anne she's questioning her vocation, given her frustrations with her dance career. She mentions a boy she used to date ("I Left Him There"). Sister Robert Anne admits to some of her own uncertainties, but knows they have both made the right choice.
Sister Robert Anne gets a call on her cell phone from Sister Amnesia, who is in the dressing room trying to warn Robert Anne that Reverend Mother has discovered the money. Too late! She has found the money in Sister Robert Anne's locker and confronts her. Sister Robert Anne explains the whole story about the ransom and volunteers to return the money knowing of Reverend Mother's attitude about the evils of gambling. Much to Robert Anne's surprise, Reverend Mother says that she forgot to mention the blessings of gambling and tells her to put the money back in the dressing room.
Sister Hubert and Reverend Mother discuss the history of the showgirl ("Sin City Sue"), inspiring another vaudeville routine ("More Shtick"). Sister Hubert and Reverend Mother hawk their "Sin City Souvenirs" and sing a duet ("Double or Nothin'").
Sister Amnesia rushes in with Sister Mary Annette. Apparently, Sister Mary Annette was off auditioning for the puppet musical Avenue Q, and they offered her part ("A Little Goes a Long Way").
No show of the Sisters' would be complete without an appearance by "The Saint Andrews Sisters of Hoboken" and this time they are California dreaming ("Hollywood 'n' Vinyl"). They end the scene with "More Shtick." Left alone onstage, Sister Robert Anne belts out a big number ("Why Sing a Ballad When You Can Belt a Show Tune").
Returning, the Sisters are stunned to learn that the Hoboken parishioner who talked them into coming to Las Vegas for $10,000 had actually accepted a challenge from the owner of the casino. The owner bet $50,000 that the Sisters would refuse to appear. They are furious and consider suing the owner, who turns out to be a former student expelled by Reverend Mother years before. Sister Hubert coolly takes charge, saying they'll do something that people who win money in Vegas never do: take the $10,000, plus the money Sister Amnesia won, and head for home. They all don Village People hats and sing "Take the Money and Run (T-T-M-'N'-R)". Waving good-by to the audience, the Sisters sing a final reprise of "Life Is a Game of Chance."