I second the Grand Canyon rim-to-rim. Many years ago I did it in one day (north to south) and I will never forget it.

The Muir Trail is a classic, and for years I resisted it, but when I did it I was mighty glas to have done it. It is just long enough to feel like a long trip, but is within the range of a normal person's vacation time. And I doubt there is a more scenic on-trail route anywhere. A mid-August start worked very well for me, weather-wise.

Any week-long cross-country trip in the Sierra is wonderful. For those who are non-Californians, I highly recommend doing one week at least in the Sierra, just so you know what it's like. Going off-trail is so much easier in the Sierra than anywhere else I've ever been that is almost a completely different concept.

And here's a Legacy Hike that I hope to do someday - a partly off-trail, partly on trip down the spine of the Sierra covering the entire roadless stretch - starting from Highway 120 in Yosemite and ending around Kennedy meadows in the south. At an enjoyable pace, the route I have imagined would take probably a month or so, and you'd never see a road the whole time if you arrange for resupply to be brought in to you (packers or helpful friends or guide services).