Perhaps a corrupt eBook file. Could be cured by archiving and downloading it again. If this is the cause of your problem the most recent eBook would be the most likely culprit.
Perhaps a corrupt ClientAPI.db and/or ClientAPIalt.db file. I believe the application will rebuild a "missing" database, but I'd recommend moving or renaming the old files so you would be able to put them back if you try this tactic and it doesn't work. Look in the C:\Documents and Settings\Username/Application Data\Barnes & Noble\BNDesktopReader folder if your running Windows XP (might have to set Windows to not hide system files) (substitute your Windows OS log in name for "Username"). You could probably locate the equivalent folder in other Windows versions by searching for "BNDesktopReder". If the application has to rebuild this file it might want to download your B&N eBook purchases again and you might need to "add" your content from other sources again.