"Is this person part of my target audience?" is perhaps the biggest question I ask when reading over someone's critique of my work. Now, since I try to ask a cross-section of people to read my work (very scientific and engineer-like, yes I know. Hush it, Bane), this means I get varied opinions on different sections.
Something one person marks up may not be marked up by another reader. While this may come down to personal taste (which is another matter entirely), it might also come down to whether the second person is an avid reader of what you're writing. We can safely assume that someone who reads a lot of horror novels might pick up on something seemingly incongruous in a romance novel that a dedicated reader of romances wouldn't even bat an eye at.
I find that this happens mostly with tropes -- commonly accepted pieces of information that you can reasonably expect the reader to know about before they read your story. A dedicated reader of epic fantasy will probably not mark up the same things that a dedicated reader of lighter fantasy would, because the epic fantasy reader already knows the tropes.
What's this mean for the writer? Well, as I learned in the course of my MS in Technical Communication, you can only write to one audience. So you have to decide, are you going to write for casual readers or hardcore ones? Older readers or younger? Academics or non-scholars?
Heck, genres tends to already have audiences (with expectations) built in. Literary fiction assumes readers are college graduates. Fantasy assumes interest in magic, and medieval (sort of) times. Science fiction, mystery, romance, suspense, thrillers, YA, MG ... you get the picture.
My point (long-winded though it was) is that if you try to focus on more than one audience, then your book suffers as a result. For my money, I'm aiming for the science-focused reader with a college/high school education. Whether I pull it off or not is an entirely different story.
What about you? Who is your target audience?