I used to get this sort of thing a lot after moving, inserting etc a lot of data in a largish 'database'. Sometimes it seemed that I had to quit excel, perhaps re-boot the pc before I would regain all the memory that had been 'lost'. I suspected that it was also linked to using another (old) application earlier in the session. So could it be linked to something you have been doing before the problem occurred, maybe nothing to do with Excel?
Otherwise you could be suffering from 'spreadsheet bloat' or just a very large spreadsheet.
As Geoff said - "what sort of things do you have in the workbook? numbers ?? formulae ?? pivottables ?? charts ??
Is there any VBA ??...are there links to other workkbooks...
On each sheet hold Ctrl and press End. That will take you to the 'last cell'. If this takes you well to the right of the last column in use or well below the last cell then that could be contibuting to the issue.
Other things to consider:
Tools,Options,calculation,SaveExternalLinkValues
With pivot tables: Options,SaveData with table layout
Can any formulae be copied, pastespecial, values?
Ditto for Pivottables/charts
Delete any obsolete named ranges - especially if these refer to other workbooks
Consider copying your data to a new workbook for a clean start.
Thanks,
Gavin