It is not hard to trace a line from the Christian humanist philosophy of Pico's Oration on the Dignity of Man to the literary work of such figures as Shakespeare and Milton—and even C.S. Lewis.

Pico envisioned the universe as a hierarchy. Every creature had a place on an ascending and descending ladder to heaven. Humans, for instance, were slightly lower than angels but were higher than animals. God was at the top of the chain.

This idea of a hierarchical universe is both affirmed and sometimes critiqued in Shakespeare's plays. Many of his dramas deal with the unfortunate consequences of people getting out of their place in the great chain of being. Brutus, for example, oversteps himself in assassinating Caesar, a disruption portended in strange physical signs in nature. Likewise, Macbeth disrupts the order of being by assassinating Duncan, and Claudius does the same by assassinating the elder Hamlet, his king and brother. In the latter cases, this disruption of the order of being brings invading armies into the land, whereas the assassination of Caesar causes a civil war.

In other cases, most notably his treatment of women, the gender-bending Shakespeare challenges the notion that females are lower in the chain of being than men. Both reason and the embrace of Christianity were important to Pico as distinguishing humans from beasts, and a character like Portia in The Merchant of Venice shows an ability to express both a reasoned argument and a plea for mercy that rivals—or even outdoes—male abilities.

Pico believed that indulging the physical over the rational (which centrally involved obeying God's laws) lowered humans in the chain of being. In Paradise Lost, Milton illustrates Adam and Eve's fallenness through their lust for one another after eating the fruit of the tree of the knowledge of good and evil.

Pico's idea of humans as caught between the celestial and the earthly, sometimes expressed by other writers calling humans the "great amphibians," has lingered on: in the twentieth century, C.S. Lewis described humans as,

Amphibians . . . half spirit and half animal . . . as spirits they belong to the eternal world, but as animals they inhabit time.

Pico also thought that one of the great attributes that God gave humans was their ability to change and grow, something he argued angels and other celestial beings did not possess. Literature has been greatly influenced by this idea, moving from the static and unchanging "types" characteristic of medieval drama to the great characters of literature, such as Shakespeare's King Lear or Bronte's Jane Eyre, who learn and grow, often painfully, as they experience life.