A really big problem on many sites is the length of lines.
It is very difficult to read text that has too many words per line.
A recent abysmal nightmare is Apple's decision to make Mail.app (and other apps) in 10.7 oriented towards full screen as if it was running on vertically oriented mobile, but on large wide screens. Small font sizes here and we have scan lines with up to 30-40 words in some cases, which is complete insanity.
Count the words per line. If the average is much more than 12, either your columns are too wide or your fonts are too small. Here on HN is a typical example with around 24 words per line on top level articles. Bad design, but very typical on the web. However, it is at least manageable, many sites are far worse.
HTML Solution? Some advocate that columns be around 30em width: http://www.maxdesign.com.au/articles/em/