Explain SMBC — the wiki for Saturday Morning Breakfast Cereal

The Joke

In the first panel, a woman passionately declares: "People who oppose genetically engineering new incredibly tall animals oppose progress itself." A man responds with the common idiom, "Get off your high horse, Sally."

In the second panel, we see the punchline: Sally is literally sitting on top of an enormously tall, genetically engineered horse, shouting "NEVER!" down at the man who is now tiny by comparison on the ground below.

The Humor

The joke is a visual pun on the expression "get off your high horse," which normally means to stop acting superior or self-righteous. Sally is advocating for genetically engineering tall animals, and she happens to be riding a literally very high horse -- one that is presumably a product of the very genetic engineering she champions. So when told to "get off her high horse," she refuses, because she is both figuratively on her high horse (being self-righteous about progress) and literally on a high horse (a genetically engineered giant one). The comic takes the dead metaphor and resurrects it into physical reality, which is a classic SMBC comedic technique.