The tectonic shifts taking place in the world of publishing are yielding some interesting outcomes. Years ago, when I began submitting short stories with the hopes of cracking into venerable magazines such as Cemetery Dance and Fantasy & Science Fiction, attention to editorial uniformity was such a big deal. Everyone seemed to use William Shunn's "proper" manuscript format (I use it still, for the most part, by the way), and many magazine would conclude their guidelines with the dour sentiment that they would reject the work directly if it didn't adhere to the guidelines.
If you published your work online (outside of the remarkable exceptions of folks like John Scalzi, who did just that with his first novel prior to being offered a contract), then most agents and publishers wouldn't touch it. The stain of amateurism was, alas, too great for a work to even enter the slush stream.
But now, with markets like Simon451, Hydra, and Alloy Entertainment sensing an opportunity to work with (primarily) digital authors to market and publish (yes, that ordering is intentional) their writing, it seems those ideals are loosening up a little. Many of these hybrid publishers will re-brand an already proven independent success. They'll accept a work in a number of different formats, and the guidelines are less stringent.
I think this phenomenon is remarkable. It happened relatively quickly, and it illustrates just how fast a segment of the market has shifted to remove some of the traditional barriers to publication that were once pervasive. It also illustrates that content is once again king. That's not to say that professionalism and appearance don't matter, because they surely do. Your submission should still follow a rhetoric of organization and clarity that allows the reader to focus on the story, and not be distracted by typography or novelty.
But I think writers can relax a little, and focus more closely on the story. Write the work you want to read and, hopefully, your readers will agree, support you, and the piece will garner additional attention. Then, when a third party comes knocking, just send them the file and let them make sense of it. If they want it, they'll grab it, regardless of its attention to the almighty guidelines...