While it's fair to say that we are still working on hardening, Zimbra was designed from the ground up for such scale. The Zimbra architecture inherits from distributed systems expertise that was gleaned building messaging systems that today host many millions of mailboxes world-wide and Java systems that have thousands of production server CPUs within single large Telco deployments.
Of paramount importance to scaling is partitioning. Partitioning leverages "locality of reference" for both processing and data---if certain servers can be specialized to solve some subset of the bigger problem, then the essential code and data are more likely already to be in memory or close at hand on fast disk.
Nice review of the principles of scaling VLIS.
