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I think everyone develops their own organizational style with age and time. And what works for one person won't necessarily make any sense to the next person. So here's how I organize mine and you can decide if that would work for you or not.

I usually organize them by publisher, theme/character, series, date of publication, and format. For example, my Marvel box would look something like this:

Marvel
- Deadpool
-- Deadpool issues
-- Deadpool one-shots
-- Deadpool TPBs
- Spider-Man (character)
-- Spectacular Spider-Man issues
-- Ultimate Spider-Man issues
- Earth X (Series)
-- Earth X complete run
-- Universe X complete run
-- Paradise X complete run
- X-Men (character/theme)
-- Uncanny X-Men issues
-- X-Force issues
-- Wolverine issues

Then there would be a similar setup for DC and Misc. stuff. The only exception to this rule is my Transformers comics, which have separate long boxes. Those are still organized the same way as above, except there is no character/theme breakdown. It's all purely based on publication dates and book titles.