The configuration comes in two flavors:
Drupal 6.
Drupal 7.
Furthermore there are two options for each configuration:
A non drush aware option that uses wget/curl to run cron and updating the site using update.php, i.e., via a web interface.
A drush aware flavor that runs cron and updates the site using drush.
To get drush to run cron jobs the easiest way is to define your own site aliases. See the example aliases file example.aliases.drushrc.php that comes under the examples directory in the drush distribution.
Example: You create the aliases for example.com and example.net, with aliases @excom and @exnet respectively.
Your crontab should contain something like:
COLUMNS=80
DRUSH=/full/path/to/drush
*/50 * * * * $DRUSH @excom cron -q
1 2 * * * $DRUSH @exnet cron -q
This means that the cron job for example.com will be run every 50 minutes and the cron job for example.net will be run every day at 02:01 hours. Check the section 7 of the Drupal INSTALL.txt for further details about running cron.