Michelle,
I've seen a lot of different approaches, depending on what you're trying to clean up:
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Spend some time on merging duplicates, as they don't really help anyone
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Look for leads with no email address, obviously bad addresses, hard bounces, etc and either add to a static list for tracking them as dead or delete them
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Look for leads with no lead-created activity in the past 3 to 6 months, e.g. clicks on emails, form fillouts, web visits, etc. Similarly, add them to a static list or get rid of them.
I general, I prefer to add folks to supression static lists rather than delete the leads, but hopefully the above is useful.