Drupal - What are the major differences between Drush versions 3 & 4?

There's a lot of new user management stuff

• user-add-role Add a role to the specified user accounts.
• user-block Block the specified
• user(s). user-cancel Cancel a user account with the specified name.
• user-create Create a user account with the specified name.
• user-information Print information about the specified user(s).
• user-login Display a one time login link for the given user account (defaults to uid 1).
• user-password (Re)Set the password for the user account with the specified name.
• user-remove-role Remove a role from the specified user accounts.
• user-unblock Unblock the specified user(s).

The cache clear functionality has become more fine grained The backup folder for module updates now appears outside of webroot and you have greater control during updates over which modules to update (security updates only)

Check out http://docs.drush.org/ for more information.

Drush 4 features a great feature where it can act upon all the sites defined in your sites/ folder in one command. So if you run multisite you can run Drush commands against them all.