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.