There are only a number of things you can change with point and click. You can, for example, change:
- The logo at the top left corner
- Change the grouping of tabs via apps
- Tab names and labels
- Add custom links to the Home tab
- Don't think you can change the color of the standard tabs
- Enable/Disable collapsible sidebar
- Show custom sidebar components on all pages
This list is by no means exhaustive, but it will give you an idea of the kind of changes you can make using point and click.
You can, however, change the complete look and feel of your org by creating custom Visualforce pages. There is no limit (in theory) of how much customization you can do with custom Visualforce pages. The only constraints that apply in this instance are - budget, in-house skill set, and time.
Hope this helps!
P.S. I've marked my answer as a community wiki because your question will not generate a concrete answer but is good enough to deserve a community wiki that will be curated by the community.