If you plan on allowing large mailboxes, you must also plan how you're going to manage your backups. If you have many mailboxes and high quotas, you could be required to back up gigabytes or terabytes of data every night, and there might not be enough time for your system to back up all the data each night.
One way to get around the problem might be to split the store into several pieces, each on its own volume. Assuming that your server could deliver the necessary throughput, you could perform concurrent backups of each store to separate tape drives.
Another option would be to implement local continuous replication (LCR). LCR works by maintaining a copy of the store on a separate Exchange server. As soon as a transaction log is full, a copy of the log is sent to the replica server using a process known as log shipping. The replica server plays the log, and thus updates its copy of the database. You can then configure your backup software to run a backup against the replica server rather than the production server. Since no users are connected to the replica server, this would let you back up your data without having to worry about exceeding a backup window or disrupting users.
Although LCR maintains a backup copy of the information store, it is not a substitute for backups. If the data center were to burn down, you'd lose the replica server along with the production server. Likewise, a corrupt transaction log could trash the replica database, just as it could the production database. If you implement LCR, you should not rely on it as the sole means of backing up your server.