Friendship and likeness were popular subjects in classical rhetoric and humanist education in sixteenth-century England, which John Lyly aimed to anatomize in his literary debut—Euphues: The Anatomy of Wit (1578). A young Oxonian graduate, Lyly presented a challenge to the classical and biblical paradox of friendship that had been rhetorically bound up with the ideal of likeness. He, reader and contributor to the nascent form of English fiction, was aware of an active readership, and his investigation of the subject of friendship demonstrates his keenness to diversify an understanding of likeness as a variable element that goes far beyond the polar opposites of positive and negative assessments. Accordingly, this article examines Lyly’s approach to a series of problematic likeness as a rhetorical response to ideas of friendship, how he manipulates and questions the problematic, mutating ideal of likeness from different layers of rhetorical resemblance. First, he considers his readership with reference to the literary likeness between his work and contemporary subjects. Second, he rethinks the unlikely likeness between young and old. Third, he doubts the uncertain, superficial likeness between man and man. Fourth, he describes a treacherous, inconstant likeness between man and woman. Finally, he wonders at a divine likeness between man and God but elaborates upon it more as his protagonist’s practice of rhetorical persuasion.