4 days in Rome

I wouldn't do the Vatican on the first day. Even if you guys tend to 'max out' after a couple of hours, the Vatican is huge and exhausting. And then, there's St. Peter's. My inclination would be to do the Colosseum instead (although if you've locked yourselves into a non-changeable tour, that won't work) as fresh air and moving around helps beat jet lag. You would then have a nice pairing of Vatican / Trastevere, which we did on a trip a few years ago and it worked well. You could probably tuck the Pantheon in on that first day as well, depending on your energy levels. For Day 2, I'm obviously biased as I've been to the Borghese twice and never to the National Museums (and I'm a history major!) but I normally would say go to the Borghese, hands down. However, if you are more into history than art, this becomes a toss-up. I guess it boils down to whether you would like more of ancient Rome after your Ostia Antica visit, or prefer to shake things up with some breath-taking marble statues.

I don't kn owyour budget but a great way to see Rome is with a docent as a guide. We planned our Rome time by seeing Ancient, Medival, Christian, and modern Rome. The docent designed two days of sight seeing around those four elements. What a great time we had. I agree, Day 1 at the Vatican is not advisable. There is a lot to see in Rome without going to Ostia.

I agree that I'd move the Vatican to another day, and I'd consider a guide through the Vatican museums. I've done it with and without, and I think it's helpful especially for the first time. There's so much there, so they just help to make sure you hit the must-sees and don't get art-fatigued. Also, since you're a history guy, see if you can book a Scavi tour. It was a real highlight for us. Info on reservation requests here:
http://www.vatican.va/roman_curia/institutions_connected/uffscavi/documents/rc_ic_uffscavi_doc_gen-information_20090216_en.html

Since you are over Sunday, you might consider during the Appian Way since most of the traffic on the Appian Way is restricted on Sunday. Either do it on your own with public transit or use the Archaeological Bus.

I will chime in that you should move the Vatican to another day and tackle it first thing in the morning when you are fresh. With jet lag you will be unlikely to have the energy to visit it that first afternoon. My suggestion would be to keep that first day to wandering. We stayed in that same area during our visit to Rome and so many things are within walking distance: piazza navona, the pantheon, trevi fountain, spanish steps. Keep it easy. You'll have a wonderful time.

Ostia is not quite Pompeii Scavi, but it is worth it. If want to do that + Appia Antica (web site maphttp://www.parcoappiaantica.it/en/default.asp) + a
long lunch all before dinner, I'd hire a driver for the day, it will eliminate any sense of being rushed and it will eliminate all hassles. Make sure you have a map of the appia antica park so you can get the driver to take you way out to the via Appia Claudia to see a long stretch of intact aqueduct. fyi this park is very large Museo Borghese is a total must do (get your ticket a day ahead) Don't forget sunset cocktails on a roof. Minerva Hotel is my fav, but Hotel Raphael is cool to. I hear that they are opening Mussolini's Balcony in Palazzo Venezia (he stood there and d war on the UK) if it is open I would check that out. If the Wedding Cake is open the top of the steps has a great view, otherwise Pz Venezia is just a large noisy place.

My wife loved Babbingtons at the base of the Spanish steps. Not Italian but has been there for nearly 100 years so still ahs a great feel foe the wife who is a foodie

I highly recommend the Villa Borghese, I think Bernini's sculpture are INCREDIBLE, and so great to see up close. However, I haven't been to the national museum so I cannot compare with that. I don't know if your wife appreciates coffee as well as food, but if so--when you visit the Pantheon, head to Taza D'Oro and try their granita. Delicious, especially on a hot day!

if you're concerned about jet lag (it sounds like you are), then I'd bump the Vatican to another day when you're more rested. Go the the Vatican museum 45 minutes early or so, then tour the museum and exit through the "tour groups only" sign in the Sistine Chapel which dumps you inside the security for St. Peters. Saves you another line and then you can head straight into one of the greatest churches in Christendom.
Whatever you do, don't miss the Pantheon.

At the risk of giving you information overload, are you aware of this excellent website? http://www.roninrome.com/site-search Hands down the best site I've come across for Rome-specific info, as well as lots of other information that applies to the whole country (demystifying Trenitalia, for example).

Thanks to all for the input. Reworked some things and think should should be a relatively relaxed way to enjoy the big sites of the city and also enjoy wandering. Day 1 Friday Get settled into hotel and then self guided wandering around the city. Thinking we can do a big loop around centro storico, stoping at Pantheon and various other sites. Villa Borghese is a possibility here. Day 2 Saturday Ancient sites with Context tours dolce vita walk/shopping/dinner Day 3 Sunday Market tour and cooking lesson Bus or taxi to Appian Way in afternoon and dinner Day 4 Vatican with Through Eternity
Trastavere Just need to come up with a few more restuarant ideas to have in our pocket. Saw some great dishes and rooftops in roninrome. Again thanks to all. You were a big help. Appian Way question....the park looks gigantic. We likely won't get there until 4PM on Sunday. I was looking at the website but the map wasn't quite working for me. I kind of want to see the aquaduct park, and was thinking about renting bikes to do some exploring. Any other suggestions or recommedations? I think we might be too late for some of the catacombs, ect but will need to kill some time before dinner. Thanks again.