Publishing is like a maze. It's hard to tell, from the starting block, where you might end up down the road. It's important that you take the time to get the lay of the land before you jump in with both feet and end up at a dead end.
Most of us write with the goal of being published by a large traditional publisher that has good distribution. While this is an admirable goal, it's important to realize it usually takes several steps to land a big publisher. The vast majority of large publishers DO NOT accept unagented, unsolicited manuscripts. While you can still choose to send one, it will likely be thrown out with the lunch wrappers and empty coffee cups. The big houses simply don't have time to read these manuscripts. Sure, you hear stories from time to time about how a bestseller came from the slushpile at a big house. You hear these stories for one reason: They're a RARITY. It's like winning the lottery. Are you more likely to achieve financial security by taking advantage of business opportunities, learning to save and invest wisely, and sticking to a budget or by playing the lottery?
You'll often hear authors say landing an agent was as tough or tougher than landing a publisher. While this may be true, it's still important, if you want to write for the big boys, to get an agent. Not only so that the agent can get your manuscripts into the right hands, but also so that you have someone on your team when it comes to other business matters like selling foreign rights or audio rights.
Here's the plain truth: If you cannot, after targeted querying, get an agent, don't take that to mean you need to skip the step entirely and begin submitting to large publishers.
Instead, consider WHY you're having trouble landing an agent. Be honest with yourself about your writing and packaging. Try to figure out if your manuscript is marketable. Listen and catalog any advice you get from the querying process and THEN consider your next move.
It's possible that your book is right for a big house, but without the help of an agent, it might never make it to the right editor's desk. If you've written the NEXT BEST THING, it will land you an agent and it will land you a deal. But you still have to do things correctly and professionally.
DISCLAIMER: Not all books require agents. If you're submitting to a small house, you may not need one. But if you're thinking Random House or HarperCollins, you need to get an agent.