Fundamental Hole #1: "Do we really know what the caveman ate?" No, but we definitely know what they DIDN'T eat. Over-processed/refined foods cooked in vegetable oils.
Fundamental Hole #2: "What was available to cavemen was highly location-dependent." Yeah, exactly, that's why everyone who eats a Paleo diet now most likely include things that all humans in different parts of the world during the Paleolithic period ate. Coconuts, animal meat, tropical fruits, seafood, roots and tubers, etc.
Fundamental Hole #3: "We can't accurately replicate it." Well, no sh*t. I can't recall the number of times I've seen on Paleohacks alone that the Paleo diet is not about exact reenactment. It's about eating as optimally as we can with what's provided to us in this day and age. There are some things that are out of our control, such as how food is grown.
Fundamental Hole #4: "Cavemen did not live long enough." Oh my gosh. Like, dude. They didn't have medicine, vaccinations, antibiotics, surgery, etc. back then as we do now. They suffered from infections and accidents and natural disasters. Back then, natural selection optimized reproductive fitness, not longevity. The whole purpose of life was to produce offspring, and the fact that humans are still around today, I say they did a pretty damn good job of that.
Fundamental Hole #5: "10,000 years is not enough time to ensure an adequate adaptation of the human genome to properly handle the products of agriculture." Modern humans developed through this diet for almost 2.5 million years. We're not designed to eat processed/refined foods. Cordain quotes Eaton and Konner who say "the human genome has changed little over the past 60,000 years, whereas our diets have changed dramatically."
Fundamental Hole #6: "No particular food group has caused any significant change to the human digestive system." From physical anthropologist Katharine Milton at UC Berkeley: "Human ancestors about 2 million years ago routinely began to include meat in their diets to compensate for a serious decline in the quality of plant foods. It was this new meat diet, full of densely-packed nutrients, that provided the catalyst for human evolution, particularly the growth of the brain. The human digestive system is fundamentally that of a plant-eating primate, except that humans have developed a more elongated small intestine rather than retaining the huge colon of apes - a change in the human lineage which indicates a diet of more concentrated nutrients."
Fundamental Hole #7: "I highly doubt that all, or even most cavemen were able to supply roughly two-thirds of their diet with animal sources." Again, every location was different in their diets. Some were high-carb, some were high-fat. Paleo isn't about taking one tribe and saying that theirs was the superior/correct version of the Paleo diet.
Fundamental Hole #8: "They weren't trying to 'be healthy.' They were trying to survive." Do you really think humans in the Paleo period had any idea what health was? Do you think they were worried about cholesterol, stroke, etc.? Whatever food you put into your mouth now is you just "trying to survive" because energy is energy and your body needs it. But the bottom line is, they survived (and were successful) on meat and vegetables.