1. Don't assume that your manager knows how high your workload is. Your manager can't help you if she doesn't realize that there's a problem. A common mistake in this situation is to assume that your workload is so obviously high that there's no way that your manager doesn't know, and so therefore she must not care or can't do anything about it. But in reality, you're the person paying the most attention to your workload, not your manager – and she may assume that since you're not speaking up, there isn't a problem. So…
2. Talk to your manager about the situation. Pick a time when your manager isn't rushed and ask to talk about your workload. Explain that it has become unmanageable and why (for instance, that you've taken on the responsibilities of someone who left without anything being removed from your plate, or that a particular account has doubled in size in the last year). Explaining what's behind the workload increase can help because your manager may not be focused on the facts as you.
3. Suggest options. You're most likely to get the help that you need if you come prepared to talk about options. For instance, you might say, "I can do A and B, but not C. Or if C is really important, I'd want to move A off my plate to make room for it. Alternately, I can act as an adviser to Jane on C, but I can't do the work of C myself if I'm also doing A and B."
4. Frame it as a matter of making the best choices. If your manager resists making these kinds of trade-offs, you need to keep pushing the issue. Say, "I hear you that we want it all to get done, but since I'm never going to be able to get to it all, I want to make strategic choices about how I should be structuring my time, and make sure that you and I are aligned on those choices." If your manager won't help you prioritize, then come up with your own proposal for what you will and won't prioritize and ask her to tweak it or OK it.
5. Enforce boundaries. To take on something new when your plate is already full, you need to either get rid of something else or at least push it back. So if a new project comes your way, go to your manager and ask about trade-offs: "If I work on this now, it means that X and Y will have to pushed back by a week. Is that OK to do, or should we put this new work on hold until X and Y are finished first?" Or, "I can do this new project and X, or this new project and Y, but not all three in the time frame we have."
One important note: The above should work with a reasonable manager – and even with a somewhat reasonable manager. If you have a manager who listens to everything here and tells you to just find a way to get everything done, then you're working for a bad manager (or alternately, you aren't working as quickly as others in the position, in which case a good manager might push back). If that's the case, you'll need to be realistic about your circumstances and decide how you want to respond.
Alison Green writes the popular Ask a Manager blog, where she dispenses advice on career, job search, and management issues. She's also the co-author of Managing to Change the World: The Nonprofit Manager's Guide to Getting Results, and former chief of staff of a successful nonprofit organization, where she oversaw day-to-day staff management, hiring, firing, and employee development.