The film is composed of a comic series of short vignettes shot in black and white built on one another to create a cumulative effect, as the characters discuss things such as caffeine popsicles, Paris in the 1920s, and the use of nicotine as an insecticide – all while sitting around drinking coffee and smoking cigarettes.

The theme of the film is absorption in the obsessions, joys, and addictions of life, and there are many common threads between vignettes, such as the Tesla coil, medical knowledge, the suggestion that coffee and cigarettes don't make for a healthy meal (generally lunch), cousins, The Lees (Cinqué and Joie, and a mention of Spike Lee), delirium, miscommunication, musicians, the similarities between musicianship and medical skill, industrial music, acknowledged fame, and the idea of drinking coffee before sleeping in order to have fast dreams.

The visual use of black and white relates to the theme of interpersonal contrasts, as each vignette features two people who disagree completely yet manage to sit amicably at the same table.

Originally the 1989 short Coffee and Cigarettes, Memphis Version (aka Coffee and Cigarettes II) segment featured Joie Lee and Cinqué Lee as the titular twins and Steve Buscemi as Danny the barman who expounds on his theory on Elvis Presley's evil twin.

The scene also features a recounting of the urban legend that Elvis Presley made racist comments about African Americans during a magazine interview.

Alex Descas and Isaach De Bankolé are a couple of friends who meet and talk over some coffee and cigarettes.

Cate Blanchett plays herself and a fictional and non-famous cousin named Shelly, whom she meets over some coffee in the lounge of a hotel.

Molina excitedly shares with him research he came across, learning that they are distant cousins, and proposes a friendship or show business project to capitalize on this.

Hip-hop artists (and cousins) GZA and RZA of the Wu-Tang Clan drink naturally caffeine-free herbal tea and have a conversation with the waiter, Bill Murray, about the dangers of caffeine and nicotine.

William "Bill" Rice and Taylor Mead spend their coffee break having a nostalgic conversation, while Janet Baker singing "Ich bin der Welt abhanden gekommen" from Mahler's Rückert-Lieder appears from nowhere.

William Rice repeats Jack White's line, "Nikola Tesla perceived the earth as a conductor of acoustical resonance."

[6][7] William Thomas of Empire delighted in the "quirky conversations" and "almost nostalgic air", but felt the film suffered from an occasional lack of focus and an uneven structure.

[9] Philip French of The Guardian criticized several segments, but praised the three in which "people appear as versions of themselves ... Iggy Pop meeting Tom Waits; Cate Blanchett (in both roles) having a reunion with an envious cousin; Alfred Molina taking tea with Steve Coogan in Hollywood".