Diamond's overall argument is framed as a response to what he identifies in the Prologue as "Yali's question." Yali, a man from New Guinea, posed his question to Diamond when the author was visiting that country on a research excursion. The question was, essentially, why white people had more "cargo," by which he meant material goods and technology, than people like himself. Diamond could not answer the question at the time, but it formed the basis for Guns, Germs, and Steel. In Diamonds's own words, his thesis is this:
History followed different courses for different peoples because of differences between peoples' environments, not because of biological differences between peoples themselves.
As he explains, what he means by this is that European people were able to develop the technology, culture, and diseases (the "guns, germs, and steel") that enabled them to dominate the world for much of its history not because of anything supposedly "superior" about them. Rather, as he shows throughout the book, it is because Eurasia was more suitable for the development of agriculture, and the complex civilizations that it facilitated, than elsewhere. It was due to unique geographic features that Europeans went on to colonize and conquer peoples around the world.