The plot for this episode was inspired by a controversial campaign led by Kirk Cameron to insert creationist materials in pamphlets on evolution at college campuses on the anniversary of Charles Darwin's birthday. The robotic scientist, Dr. Widnar, is an anagram of Darwin.
The Flying Spaghetti Monster is a reference to the emergence of Pastafarianism (Church of the Flying Spaghetti Monster), a satirical faux-religion and social movement that promotes a light-hearted view of religion and opposes the teaching of intelligent design and creationism in public schools.
When the crew is digging for the Missing Link, Hermes finds "another one of Fry's dogs." This is a reference to the episode "Jurassic Bark," which is consistently voted the saddest episode of Futurama.
The paintings on the caves by robot cavemen is based on the Lascaux cave paintings in France.
NANDerthal is a pun mixing Neanderthal with NAND (a logic gate in processors).