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Yes, you can use fixed pixel sizes, but what if someone comes to your site who doesn't have 20/20 vision? Or more probably, you're one of those who designs/uses 1024x768 (or higher) and then uses tiny type. I have 20/20 vision and a 19" monitor and I don't like such sites. I want type I don't have to squint at! I stare at a computer too many hours a day.
Flexibility is the name of the game. Flexible design to go with most screen resolutions. Flexible fonts for easy viewing for the largest viewing audience. High contrast colors -- what about the colorblind population? Not just black/white colorblind, but red/green (more people than you think). There are plenty of reasons why your audience isn't going to be looking at your page the same way you do. In fact, MOST of your audience isn't going to see your page as you do. AOL is notorious for eating screen space and altering things. Yet (WAYYY TOO) many people still love their AOL.
Now, if you're desiging for other gamers/techies, that's one thing. But if you're desiging for the general public, an analytical cruise of the major public sites is in order. Amazon, whitehouse.gov, yahoo, ebay. What do they do that you like, what do they do that you hate, and WHY do they do what they DO?
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