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I haven't had a problem with either the Reader For PC (RFP) software or Calibre with my ereader. As said by others, I just make sure that I use one, eject my ereader, and then close it before using the other software. For simplicity, I allow the RFP software to manage the ebooks in my ereader's internal memory, while Calibre handles those on my memory card.
I haven't worried about how either program stores the ebooks on my ereader since I never work directly with the file structure of my ereader. A combination of the ereader's internal software and arranging my ebooks into collections works very well for me and allows me to easily access any ebook on my ereader.
That said, I've found Calibre's use of tags to create collections much easier to work with than RFP's method of creating collections and then dragging and dropping ebooks into them. Syncing with the RFP software tends to work very well, although the inability to directly delete synced ebooks is a slight irritant.
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