The recounted story takes place in the café de la Regence, where Moi ("Me"), a narrator-like persona (often mistakenly supposed to stand for Diderot himself), describes for the reader a recent encounter he's had with the character Lui ("Him"), referring to — yet not literally meaning — Jean-François Rameau, the nephew of the famous composer, who's engaged him in an intricate battle of wits, self-reflexivity, allegory and allusion.
Recurring themes in the discussion include the Querelle des Bouffons (the French/Italian opera battle), education of children, the nature of genius and money. The often rambling conversation pokes fun at numerous prominent figures of the time.
In the prologue that precedes the conversation, the first-person narrator frames Lui as eccentric and extravagant, full of contradictions, "a mixture of the sublime and the base, of good sense and irrationality". Effectively being a provocateur, Lui seemingly extols the virtues of crime and theft, raising love of gold to the level of a religion. Moi appears initially to have a didactic role, while the nephew (Lui) succeeds in conveying a cynical, if perhaps immoral, vision of reality.
Michel Foucault, in his Madness and Civilization, saw in the ridiculous figure of Rameau's nephew a kind of exemplar of a uniquely modern incarnation of the Buffoon.