At DrupalCon Sunnyvale 2007, Rasmus Lerdorf chided Drupal on spending over half of its request time on just the bootstrap process. As a GHOP Task , Cornil did a performance analysis of Drupal and found its two largest performance drains were the bootstrap process and the theming layer. Quite simply, Drupal spends too much time including code.
Drupal 6 has the beginnings of a solution. Page handlers, the most unused code in Drupal, can now be split out into conditional include files and the menu system is able to conditionally load just the file it needs for a given page request. Based on earlier benchmarks, just that code shuffling netted Drupal 6 a 20% performance boost. The downside, however, is that it does require the module author to explicitly specify file to be included, and the syntax for it is just a little bit annoying what with the file name and file path being separate keys on the menu handler.
Fortunately, Drupal 7's self-learning code registry system has just landed, which should obliterate most of the wasted bootstrap cost.