A: (Salome) This is a complicated question. There are many different reasons queries get rejected. It could be because of the query letter itself. If you want to see some of the great query letters that are out there (and so what you're competing against) take a look at Kristin Nelson's blog. She's a literary agent. Here's a query letter she liked. Poke around on her site to find more. It's a great resource in itself.
If it's not the query letter, it's got something to do with the manuscript. Perhaps some aspect of your set up doesn't seem like something that agent can sell. Maybe your first five pages are full of typos. Someone I know had their work looked at by Irene Goodman. Unfortunately, he made some last minute changes to his manuscript and there were two typos on the first page. She pointed them out as a sign that he wasn't committed enough. Yikes.
I think anyone who looks at a lot of manuscripts and reads a lot of books, who has experience with this sort of thing, can look at a manuscripts first few pages and know right away whether it interests them. The most common mistakes I see that tell me it will never sell are a bland opening and a flat voice. A flat voice is also the hardest thing to fix -- and to explain to someone. There are many other ways a manuscript can present itself as unsellable, as well. The agent needs to feel she can sell this book to someone on her list of publishing contacts.
You can ask yourself these checklist questions: Is my manuscript properly formatted? Is the opening compelling? Is it timely? (This is a bit harder to know, but basically is it like every other sparkly vampire book that's out there? Or is it something so different and strange that it sets fire to the agent's eyeballs? Neither of these are timely.) Have I followed the agent's specific instructions? Have I not made some mistake like spelling the agent's name wrong or incorrectly naming a character in a book I'm comparing mine to? Does this agent represent the genre I'm writing?
The best way to figure out what's wrong is to have someone who has mastered this stuff look at your manuscript. The best way to solve it is to have someone point out where it's weak. It's the difference between learning to cook from a recipe and learning to cook from a master chef. You can do it on your own, but you'll have to spend a lot of time experimenting and some luck is involved.
An important thing to know is that it's not abnormal to query 25 or more agents over a period of several months to a year. If you've done that and gotten nothing but solid rejections, you probably need to reevaluate.
A: (Tim) Agents are busy. Really, really busy. Much of their time goes on looking after existing clients -- selling books, helping with problems, meetings upon meetings upon meetings. They need new books to sell in order to keep in business, and they know that very well, but they're seriously harried. On top of that, they get heaps of submissions. Fifty new ones every day. A hundred. More. If they find a submission good enough to warrant actually reading, that usually means it's work they'll have to do after they get home -- which may well not be until 8pm or 9pm.
I've worked as an agent, and as a publisher. If one submission in 100 is of publishable quality, that's a good find. It's heart-breaking, but the vast majority of novels are unpublishable. Don't worry too much; if you're aware enough to be reading this, you're already in the top 15% or so.
Agents love books, and stories, and helping bring new writers onto the shelves. If they didn't, they wouldn't put up with the hideous hours, the massive stress, or the unreliable pay. So they really are genuinely excited to find a great new voice hiding out there. It's not just a chance of another sale; it's being part of the Great Game. However, at the moment when they open your pitch email, they're not aware that you're the rightful Next Huge Thing. You're just one of the daily dump. They're looking for an excuse to move on to the next email, so they can get through them all quickly -- without more homework. Any excuse, in fact.
Any deviation from their submission instructions? NEXT.
Said "Dear Agent"? NEXT.
Premise isn't crystal-clear? NEXT.
... etc., etc., etc.
Now, there's some stuff you can't factor in -- what the agent actually likes, what the editors s/he knows are after at the moment, tropes s/he happens to be totally sick of today, and so on. The rest of it however is down to you. Make sure your manuscript is great (and complete). Then prepare a kick-ass pitch letter which follows all your target agent's rules, is totally intriguing (without being annoying), and is absolutely free of typos. There are plenty of resources to tell you how to do it, and there are also lots of agent pitch doctors out there, so if necessary, make use of one of us. Then brace yourself, and get sending! You'll still get rejections, because of the stuff you can't factor in. But if your letter is stunning and your manuscript is great, those rejections will be reluctant -- and sooner rather than later you'll find the person who realizes that yes, you actually are the Next Huge Thing.