Now that I've forcefully grabbed you attention with such a catchy title, let me tell you what Guideline #1 is:

NEVER MAKE USERS THINK.

It's that simple. But it's that important that I deemed it appropriate to use all capitals. This must be indelibly engraved into the forefront of our designing mind!

The reasoning behind this is that people don't want to acknowledge that our website is unique. Sure, it's got a different look, but if there's a different feel than the entire World Wide Web people just won't like it. It took them this long to get their 12-year-old kids to help them understand how to get around; they don't want to learn a whole new set of rules for your site alone!

Alright, now that we've established the most important rule of User Interface design, let's move onto some proven-to-work ideas.

Use Gateway Pages

No, I'm not referring to the infamous scheme used by SEP's of filling useless pages with key words to lead people to your site. What I mean here is that if you have different forms of content to serve to different groups of people, give them the option to choose immediately.

For instance, does your site offer English, Spanish, and French? Then don't give people everything in English with a little menu at the top to toggle languages. The very first page of your site, the entrance, or 'gateway' page, should make them choose before doing anything else. The same applies for Country websites. Oh, and don't make people choose again with every visit, remember their choice with a cookie.

Search

The two main ways for people to access content within your site is to either browse through your sites navigational structure, or to just search for their topic of interest. A search feature pretty much stops being a novelty, and becomes a necessity when your site has over 25 pages.

To facilitate this, a very important guideline to follow is that you don't want to make people search for a search page. Just give it to them! On every page! Nothing elaborate, just a little text field and a button that says... you'll never guess... "search". Nothing more is needed here. If you want to give them any further options, maybe someone filters, do it on an optional "advanced search" page.