This is more of a tip than a "wisdom," but it's something not everyone knows about, so I'm posting it anyway.
First and foremost, you have to do the pre-submission research. Subbing blind won't get you anywhere, unless you're extremely lucky when it comes to random drawings. In which case, buy a lottery ticket while you're at it.
And if you want to make your pre-sub research a lot easier, do online book searches according to the publisher. Most libraries in largish municipalities offer this feature in their online catalog search: type in the name of the publisher or imprint you want to scope out, choose the "search by publisher" field, and off you go: every book by that house or imprint in the library's system. Once you've got all the books by an imprint in one place, it becomes really obvious whether they do primarily dystopian or paranormal or picture books with talking animals. It makes it much easier to tell whether your MS would be a good fit for them.
Have any of you tried this? Do you have any other tips for making pre-submission research less painful?