Appearances and Reality
In The Rez Sisters, seven women travel from their Indian reserve to Toronto in order to participate in "THE BIGGEST BINGO IN THE WORLD." Each woman has her own dreams of what winning the bingo jackpot will bring them. Annie hopes for enough money to "buy every single one of Patsy Cline's records" and "go to all the taverns and night clubs in Toronto and listen to the live music." Philomena hopes for a new toilet that is "big and wide and very white." Marie-Adele wishes for "the most beautiful incredible goddamn island in the whole goddamn world." Veronique desires "the biggest stove on the reserve." Finally, Pelajia wants to build "a nice paved road" in front of her house, since their "old chief" has done nothing to help her realize this dream. Each woman's dreams of wealth are linked to their desires to make life at Wasy more bearable—or, in the case of Marie-Adele, escape "the rez" entirely.

However, when the women arrive in Toronto, luck does not favor them. Despite the fact that Philomena plays with twenty-seven cards, she only wins $600 and the others return empty-handed after charging the bingo machine in their fury. (Marie-Adele does not return at all, dying during the bingo game.) Rather than complain about their hard luck, however, the "rez sisters'' realize that these dreams cannot be realized by chance alone and that they need to focus on the changes that they can accomplish themselves. Speaking at the funeral of Marie-Adele, Pelajia states:

Well, sister, guess you finally hit the big jackpot. Best bingo game we've ever been to in our lives, huh? You know, life's like that, I figure When all is said and done kinda silly, this business of living? But what choice do we have? When some fool of a being goes and puts us Indians plunk down in the middle of this old earth, dishes out this lot we got right now But, I figure we gotta make the most of it while we're here. You certainly did. And I sure as hell am giving it one good try. For you For me. For all of us. Promise Really.

The remaining women learn to work in order to improve their lives on "the rez": Veronique takes
care of Marie-Adele's children, Annie vows to practice her singing m order to become a star, and Pelajia accepts her position on her roof, hammering away for a better tomorrow. As Philomena tells Pelajia early in the play, “This place is too much in your blood. You can't get rid of it. And it can't get rid of you." The literal and metaphorical journey depicted in The Rez Sisters reflects the women coming to understand the importance of these words. Perhaps the clearest sign that the sisters are moving in the right direction is the final appearance of Nanabush as Pelajia works on her roof; he "dances to the beat of the hammer, merrily and triumphantly.''

Friendship
In her essay on The Rez Sisters, in Books in Canada, Carol Bolt remarks that, when seeing the play, audiences feel as if they "have been a part of an extraordinary, exuberant, life-affirming family." This reaction is due to Highway's creation of characters that reflect the value of friendship and a close community. The fact that all of the women are either sisters, half-sisters, or sisters-in-law suggests that they have known each other for a long time; throughout the play they behave in a comfortable, familiar manner, joking and gossiping with each other. Even those women who profess dislike for each other (such as Annie and Veronique) still talk to each other, realizing the fact that severing any ties between them would be worse than being annoyed by each other's idiosyncrasies.

When a war of words erupts between the women, they throw the worst insults they can imagine at each other: Philomena calls Annie a "slime"; Emily calls Annie a “slippery little slut''; Veronique tells Annie she is a "sick pervert"; Pelajia calls Marie-Adele "a spoiled brat"; Marie-Adele tells Veronique that she is like "some kind of insect, sticking insect claws into everybody's business"; and Annie mocks Pelajia for thinking that she is "Queen of the Indians." However, despite these bitter retorts, a day later they are all working together, trying to raise enough money for their trip to Toronto. And during their drive, the women confess their secret fears and try to provide each other emotional comfort. Despite their gossip and tendency to quarrel, Highway's characters share an unspoken realization that they need each other for stability and support.

Supernatural
Observing the action of the play is Nanabush, the "trickster" that plays a large role in many Native mythologies and cultures. "We have a mythology that is thousands and thousands of years old," Highway explained to Hartmut Lutz in Contemporary Challenges: Conversations with Canadian Native Authors. Highway described the trickster to the Globe and Mail's Conlogue as “central to our system of spiritual belief. It's a connection to this great energy, or God, which most people only perceive in moments of extreme crisis. Or when they are close to death, and can see into the spirit world.'' In The Rez Sisters, only Marie-Adele and Zhaboonigan can recognize Nanabush in his various disguises, suggesting that the former is "close to death" and that the latter, despite her mental handicap, is more perceptive and open to the spirit world than the other women. On her way to Toronto, Marie-Adele is confronted by Nanabush, who warns her of her upcoming death; however, her ascension into the spirit world (in the arms of the Bingo Master) proves to be a breathtaking journey. By placing Nanabush onstage for most of the play, Highway suggests that the Trickster may be fading from modern Native's memories but is in fact still very much a part of their everyday lives.