The big question that Jared Diamond is posing is an expansion of one that was asked of him. This is usually referred to as “Yali’s question,” based on a passage in which Diamond converses with a New Guinean man, Yali. Yali asks him why white people are so wealthy, or literally, why they “have so much cargo,” while black people have so little. Diamond extrapolated from this to a much broader issue: why the "developed world" went through the development phases earlier, and, by extension, how European countries conquered much of the rest of the world.

The three items in the book's title are, according to Diamond, the key elements that figure into this question. The first, guns, pertains to the technology of warfare; the second, germs, relates to the diseases and lack of resistance to them that wiped out millions of people; and the third, steel, relates to overall technological superiority. Additionally (though absent from the title), there is the question of domestication of plants, which undergirded urbanization and the related agricultural revolution. Diamond treats all of these items together, moving through different world areas and applying the main question to their relative histories.

In Guns, Germs and Steel Jared Diamond wants to know why wealthy, technologically sophisticated, industrialized societies developed first in Europe rather than in other parts of the world. Yali, a New Guinean friend of his, put the question like this: "Why is it that you white people developed so much cargo and brought it to New Guinea, but we black people had little cargo of our own?" Variations on this question have been explored by scholars for the last two centuries with various answers being put forward. These answers include the superiority of European genetics, the influence of the Graeco-Roman tradition, the impact of the Judaeo-Christian tradition (or sometimes specifically the Protestant tradition), and the relatively plural societies of the west. Diamond largely rejects many of these answers in favor of geographic and ecological factors. This question is important because of the impact the development of guns, germs and steel had on the global imperialism practiced by several European states.